U.S. patent application number 10/282411 was filed with the patent office on 2003-07-31 for method of treating depression with delta receptor agonist compounds.
Invention is credited to Chang, Kwen-Jen, Gengo, Peter J., Pendergast, William.
Application Number | 20030144299 10/282411 |
Document ID | / |
Family ID | 26990913 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030144299 |
Kind Code |
A1 |
Chang, Kwen-Jen ; et
al. |
July 31, 2003 |
Method of treating depression with delta receptor agonist
compounds
Abstract
Compositions and methods for treatment of depression or other
affective mood disorders or pathological mental and/or emotional
states, by administration to a subject suffering or susceptible to
same, of therapeutically effective delta receptor agonist
compound(s), optionally in combination with other mood
disorder-combating agents.
Inventors: |
Chang, Kwen-Jen; (Chapel
Hill, NC) ; Pendergast, William; (Durham, NC)
; Gengo, Peter J.; (Raleigh, NC) |
Correspondence
Address: |
INTELLECTUAL PROPERTY / TECHNOLOGY LAW
PO BOX 14329
RESEARCH TRIANGLE PARK
NC
27709
US
|
Family ID: |
26990913 |
Appl. No.: |
10/282411 |
Filed: |
October 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60340084 |
Oct 29, 2001 |
|
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60337887 |
Nov 2, 2001 |
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Current U.S.
Class: |
514/255.04 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/24 20180101; A61K 31/497 20130101 |
Class at
Publication: |
514/255.04 |
International
Class: |
A61K 031/495 |
Claims
We claim:
1. A method of combating a mood disorder in a subject experiencing
or susceptible to same, comprising administering to said subject an
effective amount of a therapeutic composition comprising at least
one compound selected from the group consisting of:
484950515253where G.dbd.O-alkyl, N(alkyl).sub.2, and any other
pharmaceutically acceptable esters thereof; and pharmaceutically
acceptable salts and esters thereof.
2. The method of claim 1, wherein said mood disorder comprises
depression.
3. The method of claim 1, wherein said mood disorder comprises a
pathological mental and/or emotional state.
4. The method of claim 1, wherein said mood disorder comprises
bipolar manic-depression or seasonal affective disorder.
5. The method of claim 1, wherein said therapeutic composition is
administered by an administration modality selected from the group
consisting of oral, rectal, topical, sub-lingual, mucosal, nasal,
ophthalmic, subcutaneous, intramuscular, intravenous, transdermal,
spinal, intrathecal, intra-articular, intra-arterial,
sub-arachnoid, bronchial, lymphatic, and intra-uterine
administration.
6. The method of claim 1, wherein said therapeutic composition
further comprises another mood disorder-combating agent.
7. The method of claim 6, wherein said another mood
disorder-combating agent comprises an agent selected from the group
consisting of tricyclic antidepressants, MAO inhibitors, 5-HT
agonists and antagonists, aminoketones, serotonin reuptake
inhibitors and adrenergic reuptake inhibitors.
8. A composition for combating a mood disorder in a subject
experiencing or susceptible to same, comprising at least one
compound selected from the group consisting of: 545556575859where
G.dbd.O-alkyl, N(alkyl).sub.2, and any other pharmaceutically
acceptable esters thereof; and pharmaceutically acceptable salts
and esters thereof.
9. The composition of claim 8, in a unitary dose form.
10. The composition of claim 9, wherein said unitary dose form
comprises an oral dose form.
11. The composition of claim 8, further comprising another mood
disorder-combating agent.
12. The composition of claim 11, wherein said another mood
disorder-combating agent comprises an agent selected from the group
consisting of tricyclic antidepressants, MAO inhibitors, 5-HT
agonists and antagonists, aminoketones, serotonin reuptake
inhibitors and adrenergic reuptake inhibitors.
13. A dose form comprising a patch affixable to a corporeal locus,
and containing a composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising at least
one compound selected from the group consisting of:
606162636465where G.dbd.O-alkyl, N(alkyl).sub.2, and any other
pharmaceutically acceptable esters thereof, and pharmaceutically
acceptable salts and esters thereof.
14. The dose form of claim 13, wherein said patch comprises a
transdermal patch.
15. The dose form of claim 13, wherein said patch comprises a
transmucosal patch.
16. The dose form of claim 13, wherein said composition comprises
another mood disorder-combating agent.
17. The dose form of claim 16, wherein said another mood
disorder-combating agent comprises an agent selected from the group
consisting of tricyclic antidepressants, MAO inhibitors, 5-HT
agonists and antagonists, aminoketones, serotonin reuptake
inhibitors and adrenergic reuptake inhibitors.
18. A method of combating a mood disorder in a subject experiencing
or susceptible to same, comprising administering to said subject an
effective amount of a therapeutic composition comprising a
diarylmethylpiperazine compound of the general formula: 66wherein:
Ar.sup.1 is a 5- or 6-member carbocyclic or heterocyclic aromatic
ring with atoms selected from the group consisting of carbon,
nitrogen, oxygen and sulfur, and having on a first carbon atom
thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1, Y is selected from the group consisting of:
hydrogen; halogen; C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6 haloalkyl; C.sub.1-C.sub.6
alkoxy; C.sub.3-C.sub.6 cycloalkoxy; sulfides of the formula
SR.sup.8 where R.sup.8 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
arylalkyl having a C.sub.5-C.sub.10 aryl moiety and an
C.sub.1-C.sub.6 alkyl moiety, or C.sub.5-C.sub.10 aryl; sulfoxides
of the formula SOR.sup.8 where R.sup.8 is the same as above;
sulfones of the formula SO.sub.2R.sup.8 where R.sup.8 is the same
as above; nitrile; C.sub.1-C.sub.6 acyl; alkoxycarbonylamino
(carbamoyl) of the formula NHCO.sub.2R.sup.8 where R.sup.8 is the
same as above; carboxylic acid, or an ester, amide, or salt
thereof; aminomethyl of the formula CH.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 may be the same or different, and may be
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10 together may form a
ring of 5 or 6 atoms, the ring atoms selected from the group
consisting of N and C; carboxamides of the formula
CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are the same as
above, or C.sub.2-C.sub.30 peptide conjugates thereof; and
sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above; R.sup.1 is hydrogen, halogen,
or C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; Z is selected from the group consisting of hydrogen,
hydroxyl, halogen and alkoxy; Ar.sup.2 is a 5 or 6-member
carbocyclic or heterocyclic aromatic ring with atoms selected from
the group consisting of carbon, nitrogen, oxygen and sulfur, and
having on a carbon atom thereof a substituent X X is selected from
the group consisting of hydrogen, halogen (fluorine, bromine,
chlorine, iodine), hydroxy and alkoxy; or a pharmaceutically
acceptable ester or salt thereof.
19. A therapeutic composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising one or more
diarylmethylpiperazine compounds of the general formula: 67wherein:
Ar.sup.1 is a 5- or 6-member carbocyclic or heterocyclic aromatic
ring with atoms selected from the group consisting of carbon,
nitrogen, oxygen and sulfur, and having on a first carbon atom
thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1, Y is selected from the group consisting of:
hydrogen; halogen; C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6 haloalkyl; C.sub.1-C.sub.6
alkoxy; C.sub.3-C.sub.6 cycloalkoxy; sulfides of the formula
SR.sup.8 where R.sup.8 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
arylalkyl having a C.sub.5-C.sub.10 aryl moiety and an
C.sub.1-C.sub.6 alkyl moiety, or C.sub.5-C.sub.10 aryl; sulfoxides
of the formula SOR.sup.8 where R.sup.8 is the same as above;
sulfones of the formula SO.sub.2R.sup.8 where R.sup.8 is the same
as above; nitrile; C.sub.1-C.sub.6 acyl; alkoxycarbonylamino
(carbamoyl) of the formula NHCO.sub.2R.sup.8 where R.sup.8 is the
same as above; carboxylic acid, or an ester, amide, or salt
thereof; aminomethyl of the formula CH.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 may be the same or different, and may be
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10 together may form a
ring of 5 or 6 atoms, the ring atoms selected from the group
consisting of N and C; carboxamides of the formula
CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are the same as
above, or C.sub.2-C.sub.30 peptide conjugates thereof; and
sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above; R.sup.1 is hydrogen, halogen,
or C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkynyl; Z is selected from the group consisting of hydrogen,
hydroxyl, halogen and alkoxy; Ar.sup.2 is a 5 or 6-member
carbocyclic or heterocyclic aromatic ring with atoms selected from
the group consisting of carbon, nitrogen, oxygen and sulfur, and
having on a carbon atom thereof a substituent X X is selected from
the group consisting of hydrogen, halogen (fluorine, bromine,
chlorine, iodine), hydroxy and alkoxy; or a pharmaceutically
acceptable ester or salt thereof.
20. The composition of claim 19 further comprising another mood
disorder-combating agent selected from the group consisting of
tricyclic antidepressants, MAO inhibitors, and 5-HT agonists and
antagonists, aminoketones, serotonin reuptake inhibitors and
adrenergic reuptake inhibitors.
21. A composition for combating a mood disorder in a subject
experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the general formula: 68wherein:
Ar.sup.1 is 6-member carbocyclic aromatic ring having on a carbon
atom thereof a substituent Y, wherein Y is a carboxamide of the
formula CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are both an
ethyl group; Z is selected from the group consisting of hydrogen,
hydroxyl, and alkoxy; and Ar.sup.2 is a 6-member carbocyclic
aromatic ring having on a carbon atom thereof a substituent X and
wherein X is a halogen, or a pharmaceutically acceptable ester or
salt thereof.
22. The composition according to claim 21, wherein the
diarylmethylpiperazine compound is administered in an oral dosage
form.
23. The composition according to claim 21, further comprising
another mood disorder-combating agent.
24. The composition according to claim 21, further comprising
another mood disorder-combating agent that is not a delta opioid
receptor agonist.
25. The composition of claim 23, wherein said another mood
disorder-combating agent comprises an agent selected from the group
consisting of tricyclic antidepressants, MAO inhibitors, 5-HT
agonists and antagonists, aminoketones, serotonin reuptake
inhibitors and adrenergic reuptake inhibitors.
26. A method of combating a mood disorder in a subject experiencing
or susceptible to same, comprising administering to said subject an
effective amount of a therapeutic composition comprising a
diarylmethylpiperazine compound of the general formula: 69wherein:
Ar.sup.1 is 6-member carbocyclic aromatic ring having on a carbon
atom thereof a substituent Y, wherein Y is a carboxamide of the
formula CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are both an
ethyl group; Z is selected from the group consisting of hydrogen,
hydroxyl, and alkoxy; and Ar.sup.2 is a 6-member carbocyclic
aromatic ring having on a carbon atom thereof a substituent X and
wherein X is a halogen, or a pharmaceutically acceptable ester or
salt thereof.
27. The method of claim 26, wherein the composition further
comprises another mood disorder-combating agent.
28. The method of claim 27, wherein the another mood
disorder-combating agent is selected from the group consisting of
tricyclic antidepressants, MAO inhibitors, and 5-HT agonists and
antagonists, aminoketones, serotonin reuptake inhibitors and
adrenergic reuptake inhibitors.
29. A therapeutic composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the formula: 70or a
pharmaceutically acceptable ester or salt thereof.
30. The therapeutic composition of claim 29, wherein the
composition is in an effective amount to combat a mood disorder in
a subject experiencing or susceptible to same.
31. The therapeutic composition of claim 30, wherein the
composition further comprises another mood disorder-combating
agent.
32. A therapeutic composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the formula: 71or a
pharmaceutically acceptable ester or salt thereof.
33. The therapeutic composition of claim 32, wherein the compound
is in an effective amount to combat a mood disorder in a subject
experiencing or susceptible to same.
34. The therapeutic composition of claim 33, wherein the
composition further comprises another mood disorder-combating
agent.
35. The therapeutic composition of claim 33, wherein the
composition is orally administerable.
36. A therapeutic composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the formula: 72or a
pharmaceutically acceptable ester or salt thereof.
37. The therapeutic composition of claim 36, wherein the compound
is in an effective amount to combat a mood disorder in a subject
experiencing or susceptible to same.
38. The therapeutic composition of claim 37, wherein the
composition further comprises another mood disorder-combating
agent.
39. The therapeutic composition of claim 36, wherein the
composition is orally administerable.
40. A therapeutic composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the formula: 73or a
pharmaceutically acceptable ester or salt thereof.
41. The therapeutic composition of claim 40, wherein the compound
is in an effective amount to combat a mood disorder in a subject
experiencing or susceptible to same.
42. The therapeutic composition of claim 41, wherein the
composition further comprises another mood disorder-combating
agent.
43. The therapeutic composition of claim 40, wherein the
composition is orally administerable.
44. A therapeutic composition for combating a mood disorder in a
subject experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the formula: 74or a
pharmaceutically acceptable ester or salt thereof.
45. The therapeutic composition of claim 44, wherein the compound
is in an effective amount to combat a mood disorder in a subject
experiencing or susceptible to same.
46. The therapeutic composition of claim 45, wherein the
composition further comprises another mood disorder-combating
agent.
47. The therapeutic composition of claim 44, wherein the
composition is orally administerable.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Patent Application No. 60/340,084 filed on Oct. 29, 2001 and U.S.
Provisional Patent Application No. 60/337,887 filed on Nov. 2,
2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to compositions and methods of
treatment of depression or other affective mood disorders or
pathological mental and/or emotional states, by administration to a
subject suffering or susceptible to same, of delta opioid receptor
agonist compound(s), optionally in combination with other
agents.
[0004] 2. Description of the Related Art
[0005] Depression is a difficult mental disorder to treat. Patients
having such a disorder are often reluctant to seek the medical
attention necessary to diagnose the disorder. Such reluctance is
often related to the patient's fear of the stigma associated with
seeking psychiatric help or to the patient's feeling of
worthlessness associated with depression. Moreover, once the
patients seek competent psychiatric help, it is difficult to
successfully treat the disorder through a psychoanalytic approach
alone.
[0006] In the Diagnostic and Statistical Manual of Mental
disorders, Fourth Edition, (DSM IV) published by the American
Psychiatric Association, depressive disorders are classified under
mood disorders and are divided into three types: major depressive
disorder, dysthymic disorder and depressive disorder not otherwise
specified. Major depressive disorder and dysthymic disorder are
differentiated based on chronicity, severity and persistence. In
major depression, the depressed mood must be present for two weeks.
In dysthymic disorder, the depressed mood must be present for two
weeks. In dysthymic disorder the depressed mood must be present
most days over a period of two years.
[0007] Usually, major depressive disorder is characterized by its
sharp contrast to usual functioning. A person with a major
depressive episode can be functioning and feeling normal and
suddenly develop severe symptoms of depression. By contrast, a
person with dysthymic disorder has chronic depression with less
severe symptoms than major depression.
[0008] In an effort to treat depression, a variety of
antidepressant compositions have been developed. Among these are
the selective serotonin reuptake inhibitors (SSRI), such as
sertraline (registered trademark ZOLOFT.RTM.--Pfizer), fluoxetine
(registered trademark PROZAC.RTM.--Eli Lilly), paroxetine (trade
name PAXIL.RTM.--Glaxo Smith Kline), and fluvoxamine (trade name
LUVOX.TM.). Other examples of antidepressant compositions include
tricyclic antidepressants such as those sold under the registered
trademark ELAVIL.TM. (Merck, Sharpe and Dohme); aminoketone
antidepressants such as bupropion; and lithium, a metal used to
treat bipolar disorder. However, these drugs are potent, often
generating problematic side effects such as lethargy, clouded
thinking, a lack of ability to concentrate, and sexual dysfunction.
Often, these drugs take about six to eight weeks to exhibit any
desirable therapeutic effects. This time period can be prolonged
when the correct drug or combinations of drugs has to be
determined, by trial and error before any therapeutic effects are
observed. Furthermore, current research suggests that many of these
drugs produce undesirable physiological side and it is also unknown
how these drugs may affect pediatric and adolescent patients.
[0009] Therefore, what is needed is an effective,
pharmacologically-based treatment for depression. It would also be
desirable to have a treatment that potentiates the action and
reduces the side effects of known compositions used in the
treatment of depression. Such a method of treatment is lacking in
the prior art.
SUMMARY OF THE INVENTION
[0010] The present invention relates in one aspect to a method of
combating a mood disorder in a subject experiencing or susceptible
to same, comprising administering to said subject an effective
amount of a therapeutic composition comprising a
diarylmethylpiperazine compound of the general formula: 1
[0011] wherein:
[0012] Ar.sup.1 is a 5- or 6-member carbocyclic or heterocyclic
aromatic ring with atoms selected from the group consisting of
carbon, nitrogen, oxygen and sulfur, and having on a first carbon
atom thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1,
[0013] Y is selected from the group consisting of:
[0014] hydrogen;
[0015] halogen;
[0016] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0017] C.sub.1-C.sub.6 haloalkyl;
[0018] C.sub.1-C.sub.6 alkoxy;
[0019] C.sub.3-C.sub.6 cycloalkoxy;
[0020] sulfides of the formula SR.sup.8 where R.sup.8 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, arylalkyl having a
C.sub.5-C.sub.10 aryl moiety and an C.sub.1-C.sub.6 alkyl moiety,
or C.sub.5-C.sub.10 aryl;
[0021] sulfoxides of the formula SOR.sup.8 where R.sup.8 is the
same as above;
[0022] sulfones of the formula SO.sub.2R.sup.8 where R.sup.8 is the
same as above;
[0023] nitrile;
[0024] C.sub.1-C.sub.6 acyl;
[0025] alkoxycarbonylamino (carbamoyl) of the formula
NHCO.sub.2R.sup.8 where R.sup.8 is the same as above;
[0026] carboxylic acid, or an ester, amide, or salt thereof;
[0027] aminomethyl of the formula CH.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 may be the same or different, and may be
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10 together may form a
ring of 5 or 6 atoms, the ring atoms selected from the group
consisting of N and C;
[0028] carboxamides of the formula CONR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above, or C.sub.2-C.sub.30 peptide
conjugates thereof; and
[0029] sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 are the same as above;
[0030] R.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl;
[0031] Z is selected from the group consisting of hydrogen,
hydroxyl, halogen and alkoxy;
[0032] Ar.sup.2 is a 5 or 6-member carbocyclic or heterocyclic
aromatic ring with atoms selected from the group consisting of
carbon, nitrogen, oxygen and sulfur, and having on a carbon atom
thereof a substituent X
[0033] X is selected from the group consisting of hydrogen, halogen
(fluorine, bromine, chlorine, iodine), hydroxy and alkoxy;
[0034] or a pharmaceutically acceptable ester or salt thereof.
[0035] Preferably, the Z group is positioned on the third
carbon.
[0036] While the compounds of the present invention are described
hereinafter with primary reference to diarylmethylpiperazines and
benzyl derivatives thereof, including their respective ester and
salt forms, it will be recognized that the methods of the invention
for treatment of various mental disorders may include use of a wide
variety of diarylmethylpiperazines wherein the piperazinyl ring has
an arylalkyl substituent, e.g., arylalkyl having C.sub.1-C.sub.6
alkyl or aryl moieties, wherein the aryl is a Ar.sup.2 is a 5 or
6-member carbocyclic or heterocyclic aromatic ring with atoms
selected from the group consisting of carbon, nitrogen, oxygen and
sulfur, and having on a carbon atom thereof a substituent X, where
X is selected from the group consisting of hydrogen, halogen
(fluorine, bromine, chlorine, iodine), hydroxy and alkoxy.
[0037] Another aspect of the invention relates to a method of
combating a mood disorder in a subject experiencing or susceptible
to same, comprising administering to said subject an effective
amount of a therapeutic composition comprising at least one
compound selected from the group consisting of: 234567
[0038] where G.dbd.O-alkyl, N(alkyl).sub.2, and any other
pharmaceutically acceptable esters thereof,
[0039] and pharmaceutically acceptable esters and salts of the
foregoing compounds.
[0040] The therapeutic compositions may be administered by any
suitable administrative mode, e.g., an administration modality
selected from the group consisting of oral, rectal, topical,
sub-lingual, mucosal, nasal, ophthalmic, subcutaneous,
intramuscular, intravenous, transdermal, spinal, intrathecal,
intra-articular, intra-arterial, sub-arachnoid, bronchial,
lymphatic, and intra-uterine administration.
[0041] A still further aspect of the present invention relates to a
method of combating a mood disorder in a subject experiencing or
susceptible to same, comprising administering to said subject an
effective amount of a therapeutic composition comprising at least
one compound selected from the group consisting of: 8910111213
[0042] where G.dbd.O-alkyl, N(alkyl).sub.2, and any other
pharmaceutically acceptable esters thereof,
[0043] and pharmaceutically acceptable esters and salts of the
foregoing compounds;
[0044] and another mood disorder-combating agent.
[0045] The mood disorder-combating agent may be of any suitable
type, and may include, without limitation, tricyclic
antidepressants, MAO inhibitors, 5-HT agonists and antagonists,
aminoketones, serotonin reuptake inhibitors and adrenergic reuptake
inhibitors. In one specific embodiment according to the invention,
wherein another mood disorder-combating agent is employed in the
administered therapeutic composition, such other mood
disorder-combating agent is not a diarylmethylpiperazine compound
and/or a delta opioid receptor agonist.
[0046] An additional aspect of the invention relates to a
composition for combating a mood disorder in a subject experiencing
or susceptible to same, comprising at least one compound selected
from the group consisting of 141516171819
[0047] where G.dbd.O-alkyl, N(alkyl).sub.2, and any other
pharmaceutically acceptable esters thereof; and pharmaceutically
acceptable esters and salts of the foregoing compounds. The
therapeutic composition may further include another mood
disorder-combating agent including, but not limited to, tricyclic
antidepressants, MAO inhibitors, 5-HT agonists and antagonists,
aminoketones, serotonin reuptake inhibitors and adrenergic reuptake
inhibitors.
[0048] Another aspect of the present invention relates to a
therapeutic composition for combating a mood disorder in a subject
experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the general formula: 20
[0049] wherein:
[0050] Ar.sup.1 is a 5- or 6-member carbocyclic or heterocyclic
aromatic ring with atoms selected from the group consisting of
carbon, nitrogen, oxygen and sulfur, and having on a first carbon
atom thereof a substituent Y and on a second ring carbon thereof a
substituent R.sup.1,
[0051] Y is selected from the group consisting of:
[0052] hydrogen;
[0053] halogen;
[0054] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0055] C.sub.1-C.sub.6 haloalkyl;
[0056] C.sub.1-C.sub.6 alkoxy;
[0057] C.sub.3-C.sub.6 cycloalkoxy;
[0058] sulfides of the formula SR.sup.8 where R.sup.8 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, arylalkyl having a
C.sub.5-C.sub.1o aryl moiety and an C.sub.1-C.sub.6 alkyl moiety,
or C.sub.5-C.sub.10 aryl;
[0059] sulfoxides of the formula SOR.sup.8 where R.sup.8 is the
same as above;
[0060] sulfones of the formula SO.sub.2R.sup.8 where R.sup.8 is the
same as above;
[0061] nitrile;
[0062] C.sub.1-C.sub.6 acyl;
[0063] alkoxycarbonylamino (carbamoyl) of the formula
NHCO.sub.2R.sup.8 where R.sup.8 is the same as above;
[0064] carboxylic acid, or an ester, amide, or salt thereof;
[0065] aminomethyl of the formula CH.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 may be the same or different, and may be
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 methoxyalkyl, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.5-C.sub.10 aryl, or R.sup.9 and R.sup.10 together may form a
ring of 5 or 6 atoms, the ring atoms selected from the group
consisting of N and C;
[0066] carboxamides of the formula CONR.sup.9R.sup.10 where R.sup.9
and R.sup.10 are the same as above, or C.sub.2-C.sub.30 peptide
conjugates thereof; and
[0067] sulfonamides of the formula SO.sub.2NR.sup.9R.sup.10 where
R.sup.9 and R.sup.10 are the same as above;
[0068] R.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkynyl;
[0069] Z is selected from the group consisting of hydrogen,
hydroxyl, halogen and alkoxy;
[0070] Ar.sup.2 is a 5 or 6-member carbocyclic or heterocyclic
aromatic ring with atoms selected from the group consisting of
carbon, nitrogen, oxygen and sulfur, and having on a carbon atom
thereof a substituent X
[0071] X is selected from the group consisting of hydrogen, halogen
(fluorine, bromine, chlorine, iodine), hydroxy and alkoxy;
[0072] or a pharmaceutically acceptable ester or salt thereof;
and
[0073] another mood disorder-combating agent, e.g., an additional
agent selected from the group consisting of tricyclic
antidepressants, MAO inhibitors, 5-HT agonists and antagonists,
aminoketones, serotonin reuptake inhibitors, adrenergic reuptake
inhibitors, and the like.
[0074] Another aspect of the present invention relates to a
therapeutic composition for combating a mood disorder in a subject
experiencing or susceptible to same, comprising a
diarylmethylpiperazine compound of the general formula: 21
[0075] wherein:
[0076] Ar.sup.1 is 6-member carbocyclic aromatic ring having on a
carbon atom thereof a substituent Y, wherein Y is a carboxamide of
the formula CONR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are both
an ethyl group;
[0077] Z is selected from the group consisting of hydrogen,
hydroxyl, and alkoxy; and
[0078] Ar.sup.2 is a 6-member carbocyclic aromatic ring having on a
carbon atom thereof a substituent X and wherein X is a halogen,
[0079] or a pharmaceutically acceptable ester or salt thereof.
[0080] The therapeutic composition comprising a
diarylmethylpiperazine compound of the general formula (2) may be
used alone or may be used in combination with another mood
disorder-combating agent to combat a mood disorder in a subject
experiencing or susceptible to same when administering to said
subject an effective amount of the therapeutic composition.
[0081] Various other aspects, features and embodiments of the
invention will be more fully apparent from the ensuing disclosure
and appended claims.
DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS
THEREOF
[0082] In one broad method aspect of the present invention, a
diarylmethylpiperazine compound as hereinafter more fully
described, is administered to a subject in need of treatment of a
mood disorder or other pathological emotional condition, for such
treatment.
[0083] The diarylmethylpiperazine compound may be substituted on
the piperazine ring thereof with a benzyl or other arylalkyl or
arylcarbyl group, whose aryl moiety is optionally substituted with
hydrogen, one or more halo substituents, or an alkoxy group, and
such compound or a pharmaceutically acceptable ester or salt of
such compound, is administered to a subject in need of treatment.
Such compound may be a compound of the aforementioned general
formula (1) or (2), including any compounds of the various formulae
(i)-(xxi) described hereinabove.
[0084] The invention broadly contemplates the treatment of mood
disorders and other pathological mental and emotional states,
including, without limitation, those involving depression, e.g.,
bipolar manic-depression, seasonal affective disorder, etc. The
treatment in accordance with the invention may advantageously
utilize mono-therapy treatment, involving compounds of the
invention as singular therapeutic agents in administered
therapeutic compositions, or co-therapy treatment, wherein a
compound in accordance with the present invention is administered
contemporaneously, e.g., simultaneously, or sequentially, with
another therapeutic agent. As an illustrative example of such
co-therapy treatment, bipolar manic depression is treated by
co-therapy involving administration of lithium chloride and a
diarylmethylpiperazine compound of the invention.
[0085] In a particularly preferred method aspect of the invention,
depression is treated by administering to a subject in need of such
treatment an effective amount of a compound of formulae (i)-(xxi)
or a pharmaceutically acceptable ester or salt thereof.
[0086] Examples of pharmaceutically acceptable esters of compounds
of formulae (1) and (2) include carboxylic acid esters of the
hydroxyl group in the compounds of formula (1) and (2) where
Z.dbd.OH in which the non-carbonyl moiety of the carboxylic acid
portion of the ester grouping is selected from straight or branched
chain alkyl (e.g. n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g.
methoxymethyl), arylalkyl (e.g. benzyl), aryloxyalky (e.g.
phenoxymethyl), and aryl (e.g. phenyl); alkyl-, aryl-, or
arylalkylsulfonyl (e.g. methanesulfonyl); amino acid esters (e.g.
L-valyl or L-isoleucyl); dicarboxylic acid esters (e.g.
hemisuccinate); carbonate esters (e.g. ethoxycarbonyl); carbamate
esters (e.g. dimethylaminocarbonyl, (2-aminoethyl)aminocarbonyl);
and inorganic esters (e.g. mono- , di- or triphosphate).
[0087] Examples of pharmaceutically acceptable salts of the
compounds of formulae (1) and (2) include salts derived from an
appropriate base, such as an alkali metal (for example, sodium,
potassium), an alkaline earth metal (for example, calcium,
magnesium), ammonium and NR'.sub.4.sup..sup.+ (wherein R' is
C.sub.1-C.sub.4 alkyl). Pharmaceutically acceptable salts of an
amino group include salts of: organic carboxylic acids such as
acetic, lactic, tartaric, malic, lactobionic, fumaric, and succinic
acids; organic sulfonic acids such as methanesulfonic,
ethanesulfonic, isethionic, benzenesulfonic and p-toluenesulfonic
acids; and inorganic acids such as hydrochloric, hydrobromic,
sulfuric, phosphoric and sulfamic acids. Pharmaceutically
acceptable salts of a compound having a hydroxyl group consist of
the anion of said compound in combination with a suitable cation
such as Na.sup.+, NH.sub.4.sup.+, or NR.sub.4.sup.+(wherein R' is
for example a C.sub.1-4 alkyl group).
[0088] For therapeutic use, salts of the compounds of formulae
(i)-(xxi) will be pharmaceutically acceptable, i.e., they will be
salts derived from a pharmaceutically acceptable acid or base.
However, salts of acids or bases that are not pharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound. All salts,
whether or not derived from a pharmaceutically acceptable acid or
base, are within the scope of the present invention.
[0089] The delta opioid receptor binding compound employed in the
broad practice of the invention may be of any suitable type, e.g.,
a diarylmethylpiperazine compound optionally substituted on the
piperazine ring with a benzyl substituent which in turn is
optionally substituted on the phenyl ring of the benzyl group with
hydrogen, alkoxy or at least one halogen substituent, or
alternatively a diarylmethylpiperazine compound substituted on the
piperazine ring with an arylalkyl group whose aryl moiety is a
pyridine ring or other heterocyclic moiety.
[0090] In one particularly preferred aspect of the invention, the
therapeutic treatment agent is a diarylmethylpiperazine compound of
formulae (i)-(xxi) or a pharmaceutically acceptable ester or salt
thereof.
[0091] As used herein, in reference to the present invention, the
term "alkyl" is intended to be broadly construed as encompassing:
(i) alkyl groups of straight-chain as well as branched chain
character; (ii) unsubstituted as well as substituted alkyl groups,
wherein the substituents of substituted alkyl groups may include
any sterically acceptable substituents which are compatible with
such alkyl groups and which do not preclude the efficacy of the
diarylmethylpiperazine compound for its intended utility (examples
of substituents for substituted alkyl groups include halogen (e.g.,
fluoro, chloro, bromo, and iodo), amino, amido, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, nitro, hydroxy, etc.); (iii)
saturated alkyl groups as well as unsaturated alkyl groups, the
latter including groups such as alkenyl-substituted alkyl groups
(e.g., allyl, methallyl, propallyl, butenylmethyl, etc.),
alkynyl-substituted alkyl groups, and any other alkyl groups
containing sterically acceptable unsaturation which is compatible
with such alkyl groups and which does not preclude the efficacy of
the diarylmethylpiperazine compound for its intended utility; and
(iv) alkyl groups including linking or bridge moieties, e.g.,
heteroatoms such as nitrogen, oxygen, sulfur, etc.
[0092] As used herein, in reference to the present invention, the
term "aryl" is intended to be broadly construed as referring to
carbocyclic (e.g., phenyl, naphthyl) as well as heterocyclic
aromatic groups (e.g., pyridyl, thienyl, furanyl, etc.) and
encompassing unsubstituted as well as substituted aryl groups,
wherein the substituents of substituted aryl groups may include any
sterically acceptable substituents which are compatible with such
aryl groups and which do not preclude the efficacy of the
diarylmethylpiperazine compound for its intended utility. Examples
of substituents for substituted aryl groups include hydrogen, one
or more of halogen (e.g., fluoro, chloro, bromo, and iodo), amino,
amido, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, nitro,
trifluoromethyl, hydroxy, hydroxyalkyl containing a C.sub.1-C.sub.4
alkyl moiety, etc.
[0093] The compounds contemplated by the invention include those of
the general formulae (1) and (2) per se, as well as physiologically
functional derivatives thereof.
[0094] By "physiologically functional derivative" is meant a
pharmaceutically acceptable salt, ether, ester or salt of an ether
or ester of the compound of the general formula (1) or (2) or any
other compound which, upon administration to the recipient, is
capable of providing (directly or indirectly) the said compound of
the general formula (1) or (2) or an active metabolite or residue
thereof. Phenolic C.sub.1-C.sub.6 alkyl ethers are a sub-class of
physiologically functional derivatives of the compounds of formulae
(i)-(xxi).
[0095] The present invention also contemplates pharmaceutical
formulations, both for veterinary and for human medical use, which
comprise as the active agent one or more compound(s) of the
invention.
[0096] In such pharmaceutical formulations, the active agent
preferably is utilized together with one or more pharmaceutically
acceptable carrier(s) therefor and optionally any other therapeutic
ingredients. The carrier(s) must be pharmaceutically acceptable in
the sense of being compatible with the other ingredients of the
formulation and not unduly deleterious to the recipient thereof.
The active agent is provided in an amount effective to achieve the
desired pharmacological effect, as described above, and in a
quantity appropriate to achieve the desired daily dose.
[0097] The formulations include those suitable for parenteral as
well as non-parenteral administration, and specific administration
modalities include oral, rectal, topical, sub-lingual, mucosal,
nasal, ophthalmic, subcutaneous, intramuscular, intravenous,
transdermal, spinal, intrathecal, intra-articular, intra-arterial,
sub-arachnoid, bronchial, lymphatic, and intra-uterine
administration.
[0098] When the active agent is utilized in a formulation
comprising a liquid solution, the formulation advantageously may be
administered parenterally. When the active agent is employed in a
liquid suspension formulation or as a powder in a biocompatible
carrier formulation, the formulation may be advantageously
administered orally, rectally, or bronchially.
[0099] When the active agent is utilized directly in the form of a
powdered solid, the active agent may advantageously administered
orally. Alternatively, it may be administered bronchially, via
nebulization of the powder in a carrier gas, to form a gaseous
dispersion of the powder that is inspired by the patient from a
breathing circuit comprising a suitable nebulizer device.
[0100] In some applications, it may be advantageous to utilize the
active agent in a "vectorized" form, such as by encapsulation of
the active agent in a liposome or other encapsulant medium, or by
fixation of the active agent, e.g., by covalent bonding, chelation,
or associative coordination, on a suitable biomolecule, such as
those selected from proteins, lipoproteins, glycoproteins, and
polysaccharides.
[0101] The formulations comprising the active agent of the present
invention may conveniently be presented in unit dosage forms and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods generally include the step of bringing the
active compound(s) into association with a carrier that constitutes
one or more accessory ingredients. Typically, the formulations are
prepared by uniformly and intimately bringing the active
compound(s) into association with a liquid carrier, a finely
divided solid carrier, or both, and then, if necessary, shaping the
product into dosage forms of the desired formulation.
[0102] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets, tablets, or lozenges, each containing a predetermined
amount of the active ingredient as a powder or granules; or a
suspension in an aqueous liquor or a non-aqueous liquid, such as a
syrup, an elixir, an emulsion, or a draught.
[0103] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine, with the active
compound being in a free-flowing form such as a powder or granules
which optionally is mixed with a binder, disintegrant, lubricant,
inert diluent, surface active agent, or discharging agent. Molded
tablets comprised of a mixture of the powdered active compound with
a suitable carrier may be made by molding in a suitable
machine.
[0104] A syrup may be made by adding the active compound to a
concentrated aqueous solution of a sugar, for example sucrose, to
which may also be added any accessory ingredient(s). Such accessory
ingredient(s) may include flavorings, suitable preservative, agents
to retard crystallization of the sugar, and agents to increase the
solubility of any other ingredient, such as a polyhydroxy alcohol,
for example glycerol or sorbitol.
[0105] Formulations suitable for parenteral administration
conveniently comprise a sterile aqueous preparation of the active
compound, which preferably is isotonic with the blood of the
recipient (e.g., physiological saline solution). Such formulations
may include suspending agents and thickening agents and liposomes
or other microparticulate systems which are designed to target the
compound to blood components or one or more organs. The
formulations may be presented in unit-dose or multi-dose form.
[0106] Nasal spray formulations comprise purified aqueous solutions
of the active compounds with preservative agents and isotonic
agents. Such formulations are preferably adjusted to a pH and
isotonic state compatible with the nasal mucous membranes.
[0107] Formulations for rectal administration may be presented as a
suppository with a suitable carrier such as cocoa butter,
hydrogenated fats, or hydrogenated fatty carboxylic acids.
[0108] Ophthalmic formulations are prepared by a similar method to
the nasal spray, except that the pH and isotonic factors are
preferably adjusted to match that of the eye.
[0109] Topical formulations comprise the active compound dissolved
or suspended in one or more media, such as mineral oil, petroleum,
polyhydroxy alcohols, or other bases used for topical
pharmaceutical formulations.
[0110] Transdermal formulations may be prepared by incorporating
the active agent in a thixotropic or gelatinous carrier such as a
cellulosic medium, e.g., methyl cellulose or hydroxyethyl
cellulose, with the resulting formulation then being packed in a
transdermal device adapted to be secured in dermal contact with the
skin of a wearer.
[0111] In addition to the aforementioned ingredients, formulations
of this invention may further include one or more accessory
ingredient(s) selected from diluents, buffers, flavoring agents,
binders, disintegrants, surface active agents, thickeners,
lubricants, preservatives (including antioxidants), and the
like.
[0112] Depending on the specific condition to be treated, animal
subjects may be administered compounds of the present invention at
any suitable therapeutically effective and safe dosage, as may
readily be determined within the skill of the art, and without
undue experimentation.
[0113] In general, while the effective dosage of compounds of the
invention for therapeutic use may be widely varied in the broad
practice of the invention, depending on the specific condition
involved, as readily determinable within the skill of the art,
suitable therapeutic doses of the compounds of the invention, for
each of the appertaining compositions described herein, and for
achievement of therapeutic benefit in treatment of each of the
conditions described herein, will be in the range of 10 micrograms
(.mu.g) to 100 milligrams (mg) per kilogram body weight of the
recipient per day, preferably in the range of 50 .mu.g to 75 mg per
kilogram body weight per day, and most preferably in the range of
100 .mu.g to 50 mg per kilogram body weight per day. The desired
dose is may be presented as two, three, four, five, six, or more
sub-doses administered at appropriate intervals throughout the day.
These sub-doses may be administered in unit dosage forms, for
example, containing from 10 .mu.g to 1000 mg, preferably from 50
.mu.g to 500 mg, more preferably from 50 .mu.g to 250 mg, and most
preferably from 50 .mu.g to 10 mg of active ingredient per unit
dosage form.
[0114] The mode of administration and dosage forms will of course
affect the therapeutic amounts of the compounds which are desirable
and efficacious for the given treatment application.
[0115] For example, orally administered dosages typically are at
least twice, e.g., 2-10 times, the dosage levels used in parenteral
administration methods, for the same active ingredient. In oral
administration, dosage levels for compounds of the present
invention may be on the order of 5-200 mg/70 kg body weight/day. In
tablet dosage forms, typical active agent dose levels are on the
order of 10-100 mg per tablet.
[0116] The following examples are illustrative of synthetic
procedures that may be advantageously utilized to make compounds of
the present invention.
EXAMPLE 1
[0117] 22
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-
-3-hydroxybenzyl)-N,N-diethylbenzamide
[0118] A solution of 3-bromophenol (400 g, 2.31 mol),
tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole
(346 g, 5.08 mol) in 5000 mL of dichloromethane was stirred
overnight at room temperature. The reaction solution was poured
into 2000 mL of water and the layers were separated. The organic
layer was washed with 1N aqueous sodium hydroxide solution
(3.times.1500 mL) and water (2.times.1500 mL) before passing
through a pad of silica gel (400 g, silica 60, 230-400 mesh). The
silica gel was washed with dichloromethane (2.times.500 mL), the
filtrates were combined and the solvent removed under reduced
pressure to give 669 g (98.4%) of
3-(bromophenoxy)-tert-butyldimethylsila- ne as a clear pale yellow
liquid. NMR (300 MHz, CDCl.sub.3): .delta. 0.2 (s,6H); 1.0 (s,9H);
6.75 (m,1H); 7.0 (br s, 1H); 7.1 (m,2H).
[0119] 3-tert-Butyldimethylsilyloxyphenylmagnesium bromide was
formed by the slow addition of a mixture
3-bromophenoxy-tert-butyldimethylsilane (27.3 g, 92.6 mmol) and
dibromoethane (3.45 g, 18.4 mmol) in 100 mL of inhibitor-free
anhydrous tetrahydrofuran to a solution of magnesium turnings (3.57
g, 147 mmol) in 200 mL of inhibitor-free anhydrous tetrahydrofuran
at reflux. After stirring for one hour at reflux the light brown
clear mixture was cooled to room temperature.
[0120] 4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was
dissolved/suspended in toluene (1200 mL, dimethylformamide (0.15
mL) added and the suspension stirred during the dropwise addition
of thionyl chloride (53.5 mL, 87.2 g, 0.73 mol). The reaction
mixture was heated to reflux under nitrogen and stirred for 2 h,
during which time much, but not all of the aldehydo-acid passed
into solution. A further quantity of thionyl chloride (20 mL, 32.6
g, 0.27 mol) was added and reflux continued overnight. The clear
reaction mixture was evaporated, and the residue dissolved in
anhydrous tetrahydrofuran (1500 mL). The solution was cooled in an
ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol (2.5
equivalents)) was added dropwise to the stirred solution. The
ice-bath was removed and stirring continued for 2.5 h. The reaction
mixture was filtered to remove the white crystalline diethylamine
hydrochloride by-product. The crystals were washed with ethyl
acetate (2.times.600 mL), and the washings set aside. The
tetrahydrofuran filtrate was evaporated, and the residue dissolved
in the ethyl acetate washings. The solution was washed sequentially
with 1 M-hydrochloric acid (2.times.600 mL), water 2.times.300 mL),
dilute sodium carbonate solution (saturated:H.sub.2O, 1:1,
2.times.600 mL), water (2.times.300 mL) and saturated sodium
chloride solution (300 mL). The organic layer was separated, dried
over anhydrous sodium sulfate and evaporated to yield
4-formyl-N,N-diethylbenz- amide as a pale brown oil, which was used
without further purification. (Yield 115.7 g, 84%)
[0121] In a 1000 mL round bottom flask fitted with a condenser and
Dean-Stark trap were combined 4-formyl-N,N-diethylbenzamide (9.50
g, 46.3 mmol), benzotriazole (5.51 g, 46.3 mmol), and
(2R,5S)-1-allyl-2,5-dimethy- lpiperazine (7.15 g, 46.3 mmol,
Chirotech Technology, Ltd., Cambridge, England) with 400 mL of
toluene. The reaction was heated to reflux under nitrogen until no
additional water was observed in the trap (ca. 2 hours). The
reaction was cooled to room temperature and concentrated under
vacuum to leave a volume of approximately 50 mL. Anhydrous
tetrahydrofuran (100 mL) was added to the flask under nitrogen with
stirring to dissolve all residue. The solution of benzotriazole
adduct was added to the solution of
3-tert-butyldimethylsilyloxyphenylmagnesium bromide (above) at room
temperature via double-ended needle. After stirring for 2 hours,
the reaction was quenched by addition of 20 mL of saturated aqueous
ammonium chloride. Anhydrous magnesium sulfate was added and the
reaction was filtered. Solvent was removed under vacuum and the
residue was redissolved in 800 mL of ethyl acetate. The ethyl
acetate solution was washed with 4.times.200 mL of 1 M sodium
hydroxide, 200 mL of water, and 200 mL of saturated aqueous sodium
chloride. The organic layer was dried over anhydrous magnesium
sulfate and the solvent was removed to give 32.7 g of dark oil. The
oil was dissolved in 250 mL of tetrahydrofuran and 250 mL of 3 M
hydrochloric acid and stirred for 2 hours at room temperature. The
reaction solution was extracted with 3.times.250 mL of 2:1 diethyl
ether/ethyl acetate. Ethyl acetate (300 mL) was added to the
aqueous layer and pH was adjusted to 8 with aqueous sodium
hydroxide. Layers were separated and the aqueous portion was
extracted with another 3.times.300 mL of ethyl acetate. The
combined organic extracts were washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, and the solvent was
removed under vacuum to give 12.4 g of brown residue. The residue
was purified by chromatography on 300 g of silica gel, eluting with
a gradient of 1-15% ethanol in dichloromethane, to give 5.54 g of
4-((alpha-R)-alpha-((2S,5R)-
-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide
as a colorless gum (27% from 4-formyl-N,N-diethylbenzamide).
[0122]
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)-N,N-diethylbenzamide (0.87 g, 2.0 mmol) was dissolved
in methylene chloride (10 mL) and triethylamine (0.919 mL, 0.667 g,
6.6 mmol) was added. N-Phenyl bis(trifluoromethanesulfonimide)
(0.785 g, 2.2 mmol) was added and the reaction mixture was sealed
under nitrogen and stirred at room temperature overnight. The
reaction mixture was evaporated to dryness, the residue dissolved
in ethyl acetate (20 mL), and the solution extracted with 5% sodium
carbonate solution (2.times.15 mL). The organic layer was
separated, dried over anhydrous sodium sulfate and evaporated to
yield a viscous amber oil. The residue was dissolved in methylene
chloride (5 mL), applied to a column of silica gel (4.times.30 cm),
and eluted with ethanol/methylene chloride (2:98 v/v). Pure
fractions containing desired product, as evidenced by t.l.c.
(silica gel, EM60F.sub.254, 2% NH.sub.4OH in ethyl acetate,
R.sub.f=0.78) were evaporated to dryness to yield
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-di-
methyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenza-
mide (0.72 g) as a yellow/amber oil. .sup.1H NMR (CDCl.sub.3, 500
MHz); .delta. 1.00 (d, J=6.2 Hz, 3H); 1.12 (br m, 3H); 1.21 (d,
J=6.1 Hz, 3H); 1.25 (br m, 3H); 1.83 (t, J=10.6 Hz, 1H); 2.60 (m,
3H); 2.91 (dd J=11.4, 2.7, 1H); 3.02 (m, 1H); 3.18 (br s, 2H); 3.28
(br m, 2H); 3.46 (dd, J=13.7, 5.5 Hz, 1H); 3.55 (br m, 2H); 5.25
(m, 2H); 5.31 (s, 1H); 5.88 (m, 1H); 7.02 (d, J=7.7 Hz, 1H); 7.05
(s, 1H); 7.23 (m, 2H); 7.32 (d, J=8.1 Hz, 2H); 7.40 (d, J=8.1 Hz,
2H); 7.46 (t, J=7.9 Hz, 1H).
[0123] A solution of
4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-pi-
perazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide
(0.72 g, 1.286 mmol) and thiosalicylic acid (234.7 mg, 1.522 mmol)
in anhydrous tetrahydrofuran (4 mL) was stirred under nitrogen for
3 h at room temperature with a catalyst solution prepared by
dissolution of bis(dibenzylidineacetone)palladium (36.46 mg, 0.0634
mmol) and 1,4-bis(diphenylphosphino)butane (27.04 mg, 0.0634 mmol)
in tetrahydrofuran (0.5 mL). The reaction mixture was evaporated to
dryness, the residue dissolved in a mixture of ethyl acetate/ether
(1:3, 20 mL) and extracted with 5% sodium carbonate solution
(2.times.15 mL). The organic layer was diluted with two volumes of
pentane and extracted with 3M-hydrochloric acid (5.times.4 mL). The
aqueous solution was adjusted to pH 9-10 with concentrated ammonia
solution and extracted with methylene chloride (3.times.10 mL). The
combined organic extracts were dried over anhydrous sodium sulfate
and evaporated to yield 4-((alpha-R)-alpha-((2S,-
5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-d-
iethylbenzamide as a brittle pale yellow foam (0.63 g). The product
showed a single spot on thin layer chromatography (silica gel,
EM60F.sub.264, 2% NH.sub.4OH in ethyl acetate, R.sub.f=0.33).
.sup.1H NMR (CDCl.sub.3, 500 MHz); .delta. 0.95 (d, J=6 Hz, 3H);
1.13 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.26 (br m, 3H); 1.50 (t,
J=9.7 Hz, 1H); 2.31 (m, 1H); 2.64 (dd J=11.3, 2.5, 1H); 2.71
(m,1H); 2.95 (m, 1H); 3.29 (br m, 2H); 3.56 (br m, 2H); 5.43 (s,
1H); 7.04 (m, 1H); 7.21 (d, J=7.7, 1H); 7.24 ( dd, J=8.2, 2.2 Hz,
1H); 7.34 (d, J=8.2 Hz, 2H); 7.42 (d, J=8.1 Hz, 2H); 7.48 (t, J=8
Hz, 1H).
[0124]
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoro-
methylsulfonyloxy-benzyl)-N,N-diethylbenzamide (527.6 mg, 1.0 mmol)
was dissolved in acetonitrile (4.0 mL) and sodium iodide (30 mg,
0.2 mmol) added. The suspension was stirred during the addition of
triethylamine (800 .mu.L (580.8 mg), 5.74 mmol), followed by
4-fluorobenzyl bromide (249 .mu.L, 378 mg, 2.0 mmol). The reaction
mixture was sealed under nitrogen and stirred overnight at room
temperature. The reaction mixture was evaporated to dryness and the
residue dissolved in ethyl acetate (10 mL). The organic solution
was washed with saturated aqueous sodium bicarbonate solution
(2.times.5 mL) and saturated sodium chloride solution (5 mL), dried
over anhydrous sodium sulfate, and evaporated to a golden oil (a
single spot on silica gel, EM60F.sub.264, 2% NH.sub.4OH in ethyl
acetate, R.sub.f=0.86). This intermediate
4-((alpha-R)-alpha-((2S,5-
R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfony-
loxybenzyl)-N,N-diethylbenzamide (608.9 mg) was used without
further purification. The oil was dissolved in ethanol (8 mL) and
aqueous 2.5 M (10%) sodium hydroxide solution (5 mL, 12.5 mmol) was
added. The reaction mixture was stirred at room temperature for 3.5
h, then the ethanol was removed by evaporation. The oily suspension
of the sodium salt was clarified by the addition of water (7.5 mL),
and the pH of the solution adjusted to 8.5-9 by the passage of
gaseous carbon dioxide (from dry ice). The copious white
precipitate was collected by filtration, washed well with water,
and dried under vacuum (2 mm Hg) at room temperature overnight to
yield 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobe-
nzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide as a
white solid (423.6 mg, 84%). Calc. for
C.sub.31H.sub.38FN.sub.3O.sub.2 C, 73.93; H, 7.61; N, 8.34. Found
C, 73.91; H, 7.65; N, 8.21% .sup.1H NMR (CDCl.sub.3, 300 MHz);
.delta. 1.05 (d, J=6.3 Hz, 3H); 1.07 (d, J=6.3 Hz, 3H); 1.11 (br m,
3H); 1.25 (br m, 3H); 1.97 (m, 2H); 2.53 (br m, 1H); 2.57 (br m,
1H); 2.61 (dd, J=9, 2.6 Hz, 1H); 2.65 (dd, J=9, 2.4 Hz, 1H); 3.14
(d, J=13 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.87 (d, J=13
Hz, 1H); 5.13 (s, 1H); 6.62 (s, 1H); 6.70 (m, 2H); 6.96 (t, J=8.5
Hz, 2H); 7.13 (t, J=7.8 Hz, 1H); 7.24 (m, 2H); 7.28 (d, J=8.2 Hz,
2H); 7,43 (d, J=8.1 Hz, 2H).
EXAMPLE 2
[0125] 23
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-
-3-hydroxybenzyl)-N,N-diethylbenzamide
[0126] A solution of 3-bromophenol (400 g, 2.31 mol),
tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole
(346 g, 5.08 mol) in 5000 mL of dichloromethane was stirred
overnight at room temperature. The reaction solution was poured
into 2000 mL of water and the layers were separated. The organic
layer was washed with 1N aqueous sodium hydroxide solution
(3.times.1500 mL) and water (2.times.1500 mL) before passing
through a pad of silica gel (400 g, silica 60, 230-400 mesh). The
silica gel was washed with dichloromethane (2.times.500 mL), the
filtrates were combined and the solvent removed under reduced
pressure to give 669 g (98.4%) of
3-(bromophenoxy)-tert-butyldimethylsila- ne as a clear pale yellow
liquid. NMR (300 MHz, CDCl.sub.3): .delta. 0.2 (s,6H); 1.0 (s,9H);
6.75 (m,1H); 7.0 (br s, 1H); 7.1 (m,2H).
[0127] 3-tert-Butyldimethylsilyloxyphenylmagnesium bromide was
formed by the slow addition of a mixture
3-bromophenoxy-tert-butyldimethylsilane (27.3 g, 92.6 mmol) and
dibromoethane (3.45 g, 18.4 mmol) in 100 mL of inhibitor-free
anhydrous tetrahydrofuran to a solution of magnesium turnings (3.57
g, 147 mmol) in 200 mL of inhibitor-free anhydrous tetrahydrofuran
at reflux. After stirring for one hour at reflux the light brown
clear mixture was cooled to room temperature.
[0128] 4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was
dissolved/suspended in toluene (1200 mL, dimethylformamide (0.15
mL) added and the suspension stirred during the dropwise addition
of thionyl chloride (53.5 mL, 87.2 g, 0.73 mol). The reaction
mixture was heated to reflux under nitrogen and stirred for 2 h,
during which time much, but not all of the aldehydo-acid passed
into solution. A further quantity of thionyl chloride (20 mL, 32.6
g, 0.27 mol) was added and reflux continued overnight. The clear
reaction mixture was evaporated, and the residue dissolved in
anhydrous tetrahydrofuran (1500 mL). The solution was cooled in an
ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol (2.5
equivalents)) was added dropwise to the stirred solution. The
ice-bath was removed and stirring continued for 2.5 h. The reaction
mixture was filtered to remove the white crystalline diethylamine
hydrochloride by-product. The crystals were washed with ethyl
acetate (2.times.600 mL), and the washings set aside. The
tetrahydrofuran filtrate was evaporated, and the residue dissolved
in the ethyl acetate washings. The solution was washed sequentially
with 1 M-hydrochloric acid (2.times.600 mL), water 2.times.300 mL),
dilute sodium carbonate solution (saturated:H.sub.2O, 1:1,
2.times.600 mL), water (2.times.300 mL) and saturated sodium
chloride solution (300 mL). The organic layer was separated, dried
over anhydrous sodium sulfate and evaporated to yield
4-formyl-N,N-diethylbenz- amide as a pale brown oil, which was used
without further purification. (Yield 115.7 g, 84%)
[0129] In a 1000 mL round bottom flask fitted with a condenser and
Dean-Stark trap were combined 4-formyl-N,N-diethylbenzamide (9.50
g, 46.3 mmol), benzotriazole (5.51 g, 46.3 mmol), and
(2R,5S)-1-allyl-2,5-dimethy- lpiperazine (7.15 g, 46.3 mmol,
Chirotech Technology, Ltd., Cambridge, England) with 400 mL of
toluene. The reaction was heated to reflux under nitrogen until no
additional water was observed in the trap (ca. 2 hours). The
reaction was cooled to room temperature and concentrated under
vacuum to leave a volume of approximately 50 mL. Anhydrous
tetrahydrofuran (100 mL) was added to the flask under nitrogen with
stirring to dissolve all residue. The solution of benzotriazole
adduct was added to the solution of
3-tert-butyldimethylsilyloxyphenylmagnesium bromide (above) at room
temperature via double-ended needle. After stirring for 2 hours,
the reaction was quenched by addition of 20 mL of saturated aqueous
ammonium chloride. Anhydrous magnesium sulfate was added and the
reaction was filtered. Solvent was removed under vacuum and the
residue was redissolved in 800 mL of ethyl acetate. The ethyl
acetate solution was washed with 4.times.200 mL of 1 M sodium
hydroxide, 200 mL of water, and 200 mL of saturated aqueous sodium
chloride. The organic layer was dried over anhydrous magnesium
sulfate and the solvent was removed to give 32.7 g of dark oil. The
oil was dissolved in 250 mL of tetrahydrofuran and 250 mL of 3 M
hydrochloric acid and stirred for 2 hours at room temperature. The
reaction solution was extracted with 3.times.250 mL of 2:1 diethyl
ether/ethyl acetate. Ethyl acetate (300 mL) was added to the
aqueous layer and pH was adjusted to 8 with aqueous sodium
hydroxide. Layers were separated and the aqueous portion was
extracted with another 3.times.300 mL of ethyl acetate. The
combined organic extracts were washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, and the solvent was
removed under vacuum to give 12.4 g of brown residue. The residue
was purified by chromatography on 300 g of silica gel, eluting with
a gradient of 1-15% ethanol in dichloromethane, to give 5.54 g of
4-((alpha-R)-alpha-((2S,5R)-
-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide
as a colorless gum (27% from 4-formyl-N,N-diethylbenzamide).
[0130]
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h-
ydroxybenzyl)-N,N-diethylbenzamide (4.87 g, 11.2 mmol) was
dissolved in methylene chloride (60 mL) and triethylamine (5.15 mL,
3.73 g, 37 mmol) was added. N-Phenyl
bis(trifluoromethanesulfonimide) (4.40 g, 12.3 mmol) was added and
the reaction mixture was sealed under nitrogen and stirred at room
temperature overnight. The reaction mixture was evaporated to
dryness, the residue dissolved in ethyl acetate (100 mL), and the
solution extracted with 5% sodium carbonate solution (2.times.75
mL). The organic layer was separated, dried over anhydrous sodium
sulfate and evaporated to yield a viscous amber oil. The residue
was dissolved in methylene chloride (30 mL), applied to a column of
silica gel (1000 g), and eluted with ethanol/methylene chloride
(2:98 v/v).
[0131] Pure fractions containing desired product, as evidenced by
t.l.c. (silica gel, EM60F.sub.254, 2% NH.sub.4OH in ethyl acetate,
R.sub.f=0.78) were evaporated to dryness to yield
4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2-
,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethyl-
benzamide (4.03 g) as a yellow/amber oil. .sup.1H NMR (CDCl.sub.3,
500 MHz); .delta. 1.00 (d, J=6.2 Hz, 3H); 1.12 (br m, 3H); 1.21 (d,
J=6.1 Hz, 3H); 1.25 (br m, 3H); 1.83 (t, J=10.6 Hz, 1H); 2.60 (m,
3H); 2.91 (dd J=11.4, 2.7, 1H); 3.02 (m, 1H); 3.18 (br s, 2H); 3.28
(br m, 2H); 3.46 (dd, J=13.7, 5.5 Hz, 1H); 3.55 (br m, 2H); 5.25
(m, 2H); 5.31 (s, 1H); 5.88 (m, 1H); 7.02 (d, J=7.7 Hz, 1H); 7.05
(s, 1H); 7.23 (m, 2H); 7.32 (d, J=8.1 Hz, 2H); 7.40 (d, J=8.1 Hz,
2H); 7.46 (t, J=7.9 Hz, 1H).
[0132] A solution of
4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-pi-
perazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide
(4.03 g, 7.20 mmol) and thiosalicylic acid (1.32 g, 8.52 mmol) in
anhydrous tetrahydrofuran (25 mL) was stirred under nitrogen for 3
h at room temperature with a catalyst solution prepared by
dissolution of bis(dibenzylidineacetone)palladium (204 mg, 0.355
mmol) and 1,4-bis(diphenylphosphino)butane (151 mg, 0.355 mmol) in
tetrahydrofuran (3 mL). The reaction mixture was evaporated to
dryness, the residue dissolved in a mixture of ethyl acetate/ether
(1:3, 125 mL) and extracted with 5% sodium carbonate solution
(2.times.75 mL). The organic layer was diluted with two volumes of
pentane and extracted with 3M-hydrochloric acid (5.times.25 mL).
The aqueous solution was adjusted to pH 9-10 with concentrated
ammonia solution and extracted with methylene chloride (3.times.50
mL). The combined organic extracts were dried over anhydrous sodium
sulfate and evaporated to yield 4-((alpha-R)-alpha-((2S,5R)-2,5-di-
methyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenz-
amide as a brittle pale yellow foam (3.53 g). The product showed a
single spot on thin layer chromatography (silica gel,
EM60F.sub.264, 2% NH.sub.4OH in ethyl acetate, R.sub.f=0.33).
.sup.1H NMR (CDCl.sub.3, 500 MHz); .delta. 0.95 (d, J=6 Hz, 3H);
1.13 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.26 (br m, 3H); 1.50 (t,
J=9.7 Hz, 1H); 2.31 (m, 1H); 2.64 (dd J=11.3, 2.5, 1H); 2.71 (m,
1H); 2.95 (m, 1H); 3.29 (br m, 2H); 3.56 (br m, 2H); 5.43 (s, 1H);
7.04 (m, 1H); 7.21 (d, J=7.7, 1H); 7.24 ( dd, J=8.2, 2.2 Hz, 1H);
7.34 (d, J=8.2 Hz, 2H); 7.42 (d, J=8.1 Hz, 2H); 7.48 (t, J=8 Hz,
1H).
[0133] A solution of
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperaziny-
l)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamide (3.522
g, 6.0 mmol) and sodium iodide (90 mg, 0.6 mmol) in acetonitrile
(30 mL) was stirred during the addition of triethylamine (3.0 mL,
2.186 g, 21.6 mmol) followed by 3-fluorobenzyl bromide (1.472 mL,
2.268 g, 12.0 mmol). An immediate turbidity was observed,
thickening to a white crystalline precipitate as the reaction
progressed. The reaction mixture was sealed under nitrogen and
stirred at room temperature. After 18 h the solvent was removed by
evaporation under reduced pressure and the residue partitioned
between ethyl acetate (30 mL) and saturated sodium bicarbonate
solution (10 mL). The organic layer was separated and the aqueous
portion further extracted with ethyl acetate (3.times.15 mL). The
combined extract and washings were dried over sodium sulfate, the
solution evaporated to dryness and re-dissolved in ethyl acetate
(.about.5 mL). The solution was applied to an intermediate
(4.times.15 cm) Biotage column and eluted with ethyl acetate,
collecting fractions of 20 mL. Fractions containing pure material
as evidenced by thin layer chromatography (silica, EM60F.sub.254,
developed with ethyl acetate, R.sub.f 0.9) were pooled and
evaporated to yield a yellow/orange oil (3.01 g). The oil was
dissolved in ethanol (30 mL) and aqueous sodium hydroxide solution
(10.0 mL, 2.5-M, 25 mmol) was added. The initially cloudy
suspension clarified to a yellow solution that was set aside at
room temperature for 3 h. The mixture was evaporated under reduced
pressure to remove ethanol, and evaporation continued until
condensation of water indicated complete removal of ethanol. The
cloudy suspension of the oily sodium salt of the phenol was diluted
to 20 mL with water to yield a clear yellow solution. The pH of the
strongly basic solution was adjusted to 8.5-9 by passage of carbon
dioxide gas (from dry ice) to yield a dense white flocculent
precipitate. The solid was removed by filtration and washed
thoroughly with cold water, including twice re-slurrying of the
precipitate on the sinter with fresh water. The solid was air-dried
on the sinter overnight, then dried under vacuum at 1 mm Hg at room
temperature to yield 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(-
3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide
as a white solid (2.062 g, 67%) Calc. for
C.sub.31H.sub.38FN.sub.3O.sub.2 0.5 H.sub.2O: C, 72.63; H, 7.67; N,
8.20; F, 3.71. Found C, 72.77; H, 7.52; N, 8.18; F, 3.61%. .sup.1H
NMR (CDCl3, 300 MHz); .delta. 1.05 (d, J=5.9 Hz, 6H); 1.11 (br m,
3H); 1.23 (br m, 3H); 2.00 (m, 2H); 2.59 (br m, 2H); 2.62 (d,
J=11.4 Hz, 1H); 2.68 (d, J=11.0 Hz, 1H); 3.19 (d, J=13.6 Hz, 1H);
3.28 (br m, 2H); 3.54 (br m, 2H); 3.89 (d, J=13.9 Hz, 1H); 5.01 (s,
1H); 6.15 (v br s, 1H); 6.63 (s, 1H); 6.70 (m, 2H); 6.91 (t, J=8.8
Hz, 1H); 7.07 (m, 2H); 7.14 (t, J=7.8 Hz, 1H); 7.22 (m, 1H); 7.28
(d, J=8.2 Hz, 2H); 7.44 (d, J=8.1 Hz, 2H).
[0134] The following compounds were prepared from
4-((alpha-R)-alpha-((2S,-
5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-d-
iethylbenzamide (intermediate in Example 1) by a similar
procedure.
EXAMPLE 3
[0135] 24
4-((Alpha-R)-Alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-
-3-hydroxybenzyl)-N,N-diethylbenzamide
[0136] 4-((alpha-R)-alpha-((2S
,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluor-
omethylsulfonyloxy-benzyl)-N,N-diethylbenzamide (from Example 1,
527.6 mg, 1.0 mmol) was dissolved in acetonitrile (4.0 mL) and
sodium iodide (15 mg, 0.1 mmol) added. The suspension was stirred
during the addition of triethylamine (500 .mu.L (363 mg), 3.59
mmol), followed by 2-fluorobenzyl bromide (241 .mu.L (378 mg), 2.0
mmol). The reaction mixture was sealed under nitrogen and stirred
overnight at room temperature. The reaction mixture was evaporated
to dryness and partitioned between ethyl acetate (10 mL) and
saturated aqueous sodium bicarbonate solution (2.5 mL). The
supernatant organic layer was removed, and the aqueous portion
washed with ethyl acetate (3.times.10 mL). The combined organic
extract and washings were dried over anhydrous sodium sulfate and
evaporated to a golden oil. The residue was dissolved in ethyl
acetate (7 mL), applied to a pre-packed (Biotage) column and eluted
with ethyl acetate. Pure fractions containing desired product, as
evidenced by t.l.c. (silica gel, EM60F.sub.264, 100% ethyl acetate,
R.sub.f=0.77) were evaporated to dryness to yield the intermediate
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethy-
l-4-(2-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,-
N-diethylbenzamide (610 mg), as a yellow oil, which was used
without further purification. The oil was dissolved in ethanol (7
mL) and aqueous 2.5 M (10%) sodium hydroxide solution (5 mL, 12.5
mmol) was added. The reaction mixture was set aside at room
temperature for 5 h, then the ethanol removed by evaporation. The
oily suspension of the sodium salt was clarified by the addition of
water (5 mL), and the pH of the solution adjusted to 9-10 by the
passage of gaseous carbon dioxide (from dry ice). The copious white
precipitate was washed well with water and dried under vacuum (2 mm
Hg) at room temperature overnight to yield the title compound as a
white solid (431 mg, 85.6%). Calc. for
C.sub.31H.sub.38FN.sub.3O.sub.2: C, 73.93; H, 7.61; N, 8.34; F,
3.77. Found C, 73.96; H, 7.67; N, 8.29; F, 3.75%. .sup.1H NMR
(CDCl3, 300 MHz); .delta. 1.05 (d, J=6.1 Hz, 3H); 1.09 (d, J=6 Hz,
3H); 1.12 (br m, 3H); 1.24 (br m, 3H); 1.96 (t, J=10 Hz, 1H); 2.07
(t, J=10 Hz, 1H); 2.56 (br m, 2H); 2.60 (d, J=11 Hz, 1H); 2.72 (d,
J=11 Hz, 1H); 3.29 (br m, 2H); 3.36 (d, J=14 Hz, 1H); 3.55 (br m,
2H); 3.89 (d, J=14 Hz, 1H); 5.13 (s, 1H); 6.57 (s, 1H); 6.66 (d,
J=10 Hz, 2H); 7.00 (t, J=9 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.10
(t, J=8 Hz, 1H); 7.20 (m, 1H); 7.27 (d, J=8 Hz, 2H); 7.38 (t, J=7
Hz, 1H); 7,43 (d, J=7 Hz, 2H).
EXAMPLE 4
[0137] 25
4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy-
benzyl)-N,N-diethylbenzamide
[0138] (Yield 88.5%). Calc. for C.sub.31H.sub.39N.sub.3O.sub.2 0.9
H.sub.2O: C, 74.19; H, 8.19; N, 8.37. Found C, 74.20; H, 7.88; N,
8.25%. .sup.1H NMR (CDCl3, 300 MHz); .delta. 1.03 (d, J=6.1 Hz,
3H); 1.09 (d, J=6.1 Hz, 3H); 1.12 (br m, 3H); 1.24 (br m, 3H); 1.99
(m, 2H); 2.53 (br m, 2H); 2.60 (dd, J=9, 2 Hz, 1H); 2.65 (dd, J=9,
2 Hz, 1H); 3.17 (d, J=13 Hz, 1H); 3.29 (br m, 2H); 3.55 (br m, 2H);
3.95 (d, J=13 Hz, 1H); 5.13 (s, 1H); 6.55 (s, 1H); 6.64 (mn, 2H);
7.10 (t, J=7.7 Hz, 2H); 7.13 (m, 1H); 7.24 (m, 5H); 7,45 (d, J=8.1
Hz, 2H).
EXAMPLE 5
[0139] 26
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-
-3-methoxybenzyl)-N,N-diethylbenzamide
[0140] Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH,
10 mmol)) was washed with pentane (2.times.7 mL), then
tetrahydrofuran (10 mL) added as supernatant.
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-f-
luorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide
(Example 1, 1.007 g, 2.0 mmol) was dissolved in the stirred
suspension, and when effervescence had subsided, methyl iodide (249
.mu.L, 568 mg, 4 mmol) was added. The reaction mixture was sealed
under nitrogen and stirred for 6 h at ambient temperature. The
reaction mixture was evaporated to dryness, and the residue
partitioned between ethyl acetate (15 mL) and water (5 mL). The
organic layer was separated, the aqueous portion extracted with
ethyl acetate (2.times.10 mL) and the combined organic extracts
dried over anhydrous sodium sulfate. The organic solution was
evaporated to a pale yellow gum, which on trituration and
sonication with pentane yielded
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl-
)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid
(0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc.
for C.sub.32H.sub.40FN.sub.3O.sub.2 0.25 H.sub.2O: C, 73.60; H,
7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%
.sup.1H NMR (CDCl3, 300 MHz); .delta. 1.09 (d, J=6.2 Hz, 6H,
superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br
m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H);
3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H);
6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26
(m, 5H); 7.46 (d, J=7.8 Hz, 2H).
EXAMPLE 6
[0141] 27
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0142] Method 1
[0143] a) 4-Formyl-N,N-diethylbenzamide
[0144] 4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was
dissolved/suspended in toluene (1200 mL, dimethylformamide (0.15
mL) added and the suspension stirred during the dropwise addition
of thionyl chloride (53.5 mL, 87.2 g, 0.73 mol). The reaction
mixture was heated to reflux under nitrogen and stirred for 2 h,
during which time much, but not all of the aldehydo-acid passed
into solution. A further quantity of thionyl chloride (20 mL, 32.6
g, 0.27 mol) was added and reflux continued overnight. The clear
reaction mixture was evaporated, and the residue dissolved in
anhydrous tetrahydrofuran (1500 mL). The solution was cooled in an
ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol (2.5
equivalents)) was added dropwise to the stirred solution. The
ice-bath was removed and stirring continued for 2.5 h. The reaction
mixture was filtered to remove the white crystalline diethylamine
hydrochloride by-product. The crystals were washed with ethyl
acetate (2.times.600 mL), and the washings set aside. The
tetrahydrofuran filtrate was evaporated, and the residue dissolved
in the ethyl acetate washings. The solution was washed sequentially
with 1 M-hydrochloric acid (2.times.600 mL), water 2.times.300 mL),
dilute sodium carbonate solution (saturated:H.sub.2O, 1:1,
2.times.600 mL), water (2.times.300 mL) and saturated sodium
chloride solution (300 mL). The organic layer was separated, dried
over anhydrous sodium sulfate, and evaporated to yield
4-formyl-N,N-diethylben- zamide as a pale brown oil, which was used
without further purification. (Yield 115.7 g, 84%)
[0145] b)
4-((alpha-S)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)b-
enzyl)-N,N-diethylbenzamide
[0146] A solution of 4-formyl-N,N-diethylbenzamide (51.3 g, 250
mmol), benzotriazole (29.8 g, 250 mmol) and
(2R,5S)-1-allyl-2,5-dimethylpiperazi- ne (38.6 g, 250 mmol,
Chirotech Technology, Ltd., Cambridge, England) in toluene (2500
mL) was heated under reflux under nitrogen with azeotropic removal
of water for 2.5 h. Toluene was removed gradually via the
Dean/Stark trap during this period until the residual volume of the
reaction mixture was reduced to approximately 700-800 mL. The
solution was diluted with anhydrous tetrahydrofuran (1000 mL),
cooled to .about.0.degree. C. in an ice/isopropanol bath, and
stirred under nitrogen during the addition over .about.20 min of
phenylmagnesium bromide (1.0 M in tetrahydrofuran, 500 mL, 500
mmol) through a wide-bore double-tipped needle. During the addition
a suspension of magnesium salts began to form almost immediately,
but did not become sufficiently thick to preclude efficient
stirring. Initially the suspension was a yellow ochre in color,
which persisted until about two-thirds of the Grignard reagent had
been added, when the color of the reaction mixture changed rapidly
to a ruddy brown. The ice bath was removed and the suspension
stirred at ambient temperature for 1.5 h, then quenched with
saturated aqueous ammonium chloride solution (125 mL). The yellow
suspension was stirred for 30 min, then anhydrous magnesium
chloride (125 g) added. The suspension was stirred for a further
hour and filtered. The filter cake was washed with tetrahydrofuran
(400 mL), and the combined filtrate and washings evaporated to a
thick brown oil. The residue was partitioned between ethyl acetate
(2500 mL) and aqueous sodium hydroxide solution (1.0 M, 1000 mL).
The organic layer was separated and washed successively with
1M-NaOH (3.times.1000 mL), water (3.times.1200 mL) and saturated
aqueous sodium chloride solution (750 mL). Ethyl acetate (75 mL)
was added to the partially crystallizing suspension, yielding a
thick slurry of light-colored crystals in a dark mother liquor. The
suspension was filtered, and the solid washed sparingly with cold
ethyl acetate and dried under vacuum at room temperature to yield a
slightly off-white solid (38.31 g). The dark filtrate and washings
were evaporated to a dark oil, which again partially crystallized
on standing. The residue was triturated with ethyl acetate (20 mL)
and filtered to yield a second crop of pale yellow crystals (4.04
g). Total yield of 4-((alpha-S)-alpha-((2S,-
5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide
was 42.35 g, (40.4%)
[0147] c)
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)benzyl)-N-
,N-diethylbenzamide
[0148] A solution of bis(dibenzylidineacetone)palladium (1.438 g,
2.5 mmol) and 1,4-bis(diphenylphosphino)butane (1.066 g, 2.5 mmol)
in tetrahydrofuran (20 mL) was stirred under nitrogen at room
temperature for 15 min, then added via syringe to a stirred
solution under nitrogen of
4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-
-N,N-diethylbenzamide (20.98 g, 50 mmol) and thiosalicylic acid
(9.25 g, 60 mmol) in anhydrous tetrahydrofuran (100 mL). The
reaction mixture was stirred under nitrogen for 2 h at room
temperature, then evaporated to dryness, the residue dissolved
ethyl acetate (120 mL) and diluted with ether (300 mL). The
solution was washed with dilute sodium carbonate solution
(saturated:H.sub.2O, 1:3, 3.times.200 mL). The organic solution was
diluted with pentane (800 mL) and extracted with 3M-hydrochloric
acid (5.times.40 mL), followed by M-hydrochloric acid (3.times.50
mL, alternating with water (3.times.50 mL)). The combined aqueous
extracts were filtered to remove a small amount of suspended solid
and the pH adjusted to 12 with 5-M NaOH. The resulting oily
suspension was extracted with methylene chloride (3.times.150 mL),
the combined organic extracts dried over anhydrous sodium sulfate
and evaporated to dryness to yield
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethy-
lbenzamide as a very pale yellow solid (18.07 g, 97.8%). The
product showed a single spot on thin layer chromatography (silica
gel, EM60F.sub.264, 4% NH.sub.4OH/10% EtOH in ethyl acetate,
R.sub.f=0.25). and was used without further purification. Calc. for
C.sub.24H.sub.33N.sub.3O 0.2 H.sub.2O: C, 75.24; H, 8.79; N, 10.97.
Found C, 75.24; H, 8.87; N, 10.86%.
[0149] d)
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-pi-
perazinyl)benzyl)-N,N-diethylbenzamide
[0150] A solution of
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperaziny-
l)benzyl)-N,N-diethylbenzamide (9.128 g, 24.05 mmol) in
acetonitrile (150 mL)) was added to sodium iodide (360 mg, 2.4
mmol) and stirred under nitrogen during the addition of
triethylamine (12 mL, (8.76 g), 86.6 mmol), followed by
3-fluorobenzyl bromide (5.9 mL, (9.09 g), 48.1 mmol). An immediate
turbidity was observed on addition of the fluorobenzyl bromide,
thickening to a white crystalline precipitate over one hour. The
reaction mixture was stirred under nitrogen overnight at room
temperature. The solvent was removed by evaporation, and saturated
sodium bicarbonate solution (25 mL) added to the residue. The
copious white precipitate was filtered off, washed well with water
and dried under vacuum at room temperature to give
4-((alpha-S)-alpha-((2S,5R)-2,5-dimeth-
yl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide
(10.54 g, 89.2%). Calc. for C.sub.31H.sub.38FN.sub.3O 0.2 H.sub.2O:
C, 75.79; H, 7.88; N, 8.55; F, 3.87. Found C, 75.80; H, 7.78; N,
8.49; F, 3.75%.
[0151] Method 2
[0152] a) 4-Formyl-N,N-diethylbenzamide
[0153] To a 12 L flask equipped with mechanical stirrer and cold
bath was charged 300 g (2 mol) of 4-carboxybenzaldehyde, 4.5 L of
tetrahydrofuran and 245 g (2.4 mol) of triethyl-amine. This
solution was cooled to -4.degree. C. with methanol/ice bath. To the
reaction was charged 236 g (1.9 mol) of pivaloyl chloride at a rate
that maintained the temperature below 5.degree. C. After stirring
for 2 h the resulting slurry was filtered and the filter cake was
washed with 1 L of THF. The filtrates were returned to the reactor
and cooled below -5.degree. C. Diethylamine (438 g, 6 mol) was
slowly added maintaining the temperature below 0.degree. C. The
reaction was stirred for several hours and allowed to warm. The
solvent was then removed under vacuum and the resulting residue was
dissolved in 2 L of ethyl acetate. The resulting solution was
washed with 1 L of water and the aqueous layer was back-extracted
with 2.times.500 mL ethyl acetate. The combined organic layer was
washed with 3.times.500 mL of 1 N HCl and 3.times.500 mL of
NaHCO.sub.3 (aq, sat). This solution was dried with
Na.sub.2SO.sub.4 and the solvent was removed under vacuum to give a
golden brown oil (172 g, 85%) containing .about.13% impurity by
NMR. The aldehyde was used with out further purification.
[0154] b)
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-pi-
perazinyl)benzyl)-N,N-diethylbenzamide
[0155] To a 500 mL three-necked flask was charged 5 g (24.3 mmol)
of 4-formyl-N,N-diethylbenzamide (5.8 g @ 86% purity), 4.3 g (36.6
mmol) benzotriazole, 0.05 g (0.24 mmol) 4-toluenesulfonic acid, and
125 mL toluene. The mixture was heated to reflux removing water
azeotropicly via a Dean-Stark trap. When water stopped accumulating
in the trap, 5.4 g (24.3 mmol) of
(2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl)piperazine (IRIX
Pharmaceuticals, Florence, S.C., U.S.A.) was added in 2-3 portions,
removing water between additions. The reaction was refluxed until
the theoretical amount of water was removed (2-3 h), followed by
distillation of 100 mL of toluene from the reaction. The remaining
solution was cooled below 60.degree. C. Anhydrous tetrahydrofuran
(150 mL) was added and the reaction was cooled below 10.degree. C.
Phenylmagnesium bromide (1 M in THF, 100 mL, 97.6 mmol) was charged
while maintaining the temperature between 0 and 10.degree. C. After
stirring for two hours, the reaction was quenched by addition of
100 mL of saturated aqueous ammonium chloride. After phase
separation, the aqueous layer was discarded. The organic layer was
extracted with 3.times.75 mL of 1 N HCl. The aqueous layer was
washed with 4.times.74 mL of methyl-tert.-butyl ether. The pH of
the aqueous layer was raised to 8-10 with 115 mL 2 N sodium
hydroxide. The aqueous layer was extracted with 3.times.75 mL of
methyl-tert.-butyl ether. The organic layer was washed with brine,
dried with Na.sub.2SO.sub.4 and evaporated under vacuum. The
resulting solid was dissolved in 3 v/w of hot 2-propanol. Water was
charged until a haze was observed. The solution was cooled with
stirring to room temperature. The resulting solids were filtered
and washed with 1/1 2-propanol-water (50 mL). The filter cake was
dried at 40.degree. C. to give 4.8 g (40%) of
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl-
)benzyl)-N,N-diethylbenzamide as a white solid.
[0156] The following compounds were prepared by alkylation of
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethy-
lbenzamide (from Example 6, Method 1, intermediate (c)) with the
appropriate benzyl halide in similar fashion to the process for
Example 6, Method 1, procedure (d).
EXAMPLE 7
[0157] 28
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0158] (Yield 96.4%). Calc. for C.sub.31H.sub.38FN.sub.3O: C,
76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.32; H, 7.86; N, 8.60;
F, 3.95% .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.07 (d, J=6.2 Hz,
3H); 1.10 (d, J=6.3 Hz, 3H, partially overlapped by br m, 3H); 1.23
(br m, 3H); 1.93 (m, 1H); 1.98 (dd, J=11.1, 8.3 Hz, 1H); 2.54 (br
m, 2H); 2.65 (m, 2H); 3.14 (d, J=13.1 Hz, 1H); 3.28 (br m, 2H);
3.54 (br m, 2H); 3.86 (d, J=13.1 Hz, 1H); 5.15 (s, 1H); 6.90 (t,
J=8.2 Hz, 2H); 7.20 (d, J=7.3 Hz, 2H); 7.24 (m, 2H); 7.27 (m, 1H;
partially overlapped by CHCl.sub.3); 7.29 (d, J=9.4 Hz, 2H); 7.33
(m, 2H); 7.46 (d, J=8.1 Hz, 2H).
EXAMPLE 8
[0159] 29
4-((alpha-S)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,-
N-diethylbenzamide
[0160] (Yield 71.8%). Calc. for C.sub.31H.sub.39N.sub.3O: C, 79.28;
H, 8.37; N, 8.95. Found C, 79.05; H, 8.34; N, 8.91% .sup.1H NMR
(CDCl3, 500 MHz); .delta. 1.09 (d, J=6.2 Hz, 3H); 1.12 (d, J=6.1
Hz, 3H); both doublets partially overlapped by br m, 3H); 1.24 (br
m, 3H); 1.72 (m, 1H); 1.93 (m, 1H); 2.02 (dd, J=9.3, 8.4 Hz, 1H);
2.55 (m, 2H); 2.66 (dd, J=11.1, 2.4 Hz, 1H); 2.70 (dd, J=11, 2.5
Hz, 1H); 3.18 (d, J=13.8 Hz, 1H); 3.28 (br m, 2H); 3.55 (br m, 2H);
3.92 (d, J=13.1 Hz, 1H); 5.18 (s, 1H); 7.20 (d, J=7.4 Hz, 2H,
partially overlapped by m, 1H); 7.30 (m, 9H); 7.47 (d, J=8 Hz,
2H).
EXAMPLE 9
[0161] 30
4-((alpha-S)-alpha-((2S,5R)-4-(3-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0162] (Yield 75.8%). Calc. for C.sub.31H.sub.38ClN.sub.3O: C,
73.86; H, 7.60; N, 8.34; Cl, 7.03. Found C, 73.86; H, 7.68; N,
8.37; Cl, 7.01% .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.06 (d,
J=6.2 Hz, 3H); 1.12 (d, J=6.1 Hz, 3H, overlapping br m, 3H); 1.23
(br m, 3H); 1.94 (br t, J=9.5 Hz, 1H); 2.01 (dd, J=11.1, 8.2 Hz,
1H); 2.56 (m, 2H); 2.67 (dt, J=10.5, 2.4 Hz, 2H); 3.15 (d, J=13.5
Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=13.5 Hz, 1H);
5.15 (s, 1H); 7.19 (m, 5H); 7.29 (m, 4H); 7.33 (br t, J=7.4Hz, 2H);
7.46 (d, J=8.1 Hz, 2H).
EXAMPLE 10
[0163] 31
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-methoxybenzyl)-1-piperazinyl-
)benzyl)-N,N-diethylbenzamide
[0164] (Yield 72.44%). Calc. for C.sub.32H.sub.41N.sub.3O.sub.2: C,
76.92; H, 8.27; N, 8.41. Found C, 76.98; H, 8.38; N, 8.42%. .sup.1H
NMR (CDCl3, 600 MHz); .delta. 1.07 (d, J=6.2 Hz, 3H); 1.11 (d,
J=6.1 Hz, 3H, overlapping br m, 3H); 1.23 (br m, 3H); 1.91 (br t,
J=10.2 Hz, 1H); 1.99 (dd, J=11.0, 8.6 Hz, 1H); 2.52 (br m, 2H);
2.64 (dd, J=11.5, 2.6 Hz, 1H); 2.68 (dd, J=11.1, 2.6 Hz, 1H); 3.13
(d, J=12.9 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.79 (s, 3H);
3.85 (d, J=13.5 Hz, 1H); 5.17 (s, 1H); 6.82 (d, J=8.5 Hz, 2H); 7.19
(d, J=8.3 Hz, 4H); 7.29 (m, 5H); 7.46 (d, J=8.1 Hz, 2H).
EXAMPLE 11
[0165] 32
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0166] (Yield 68.9%). Calc. for C.sub.31H.sub.38FN.sub.3O: C,
76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.35; H, 8.02; N, 8.60;
F, 3.81% .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.09 (d, J=6.1 Hz,
3H); 1.13 (d, J=6.1 Hz, 3H); (both doublets overlapped by br m,
3H); 1.24 (br m, 3H); 1.90 (br t, J=10.4 Hz, 1H); 2.08 (dd, J=10.9,
8.6 Hz, 1H); 2.56 (br m, 2H); 2.66 (dd, J=11.5, 2.7 Hz, 1H); 2.73
(dd, J=11.1, 2.4 Hz, 1H); 3.28 (br m, 2H); 3.34 (d, J=13.8 Hz, 1H);
3.54 (br m, 2H); 3.88 (d, J=13.8 Hz, 1H); 5.19 (s, 1H); 7.00 (br t,
J=9.1 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.19 (m, 3H); 7.29 (m, 5H);
7.37 (br t, J=7.1Hz, 1H); 7.46 (d, J=8.1 2H).
EXAMPLE 12
[0167] 33
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-pyridylmethyl)-1-piperazinyl-
)benzyl)-N,N-diethylbenzamide
[0168] (Yield 69.7%). Calc. for C.sub.30H.sub.38N.sub.4O 0.15
H.sub.2O: C, 76.12; H, 8.16; N, 11.84. Found C, 76.14; H, 8.36; N,
11.70%. .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.05 (d, J=6.1 Hz,
3H); 1.11 (d, J=6.2 Hz, 3H; overlapped by br m, 3H); 1.24 (br m,
3H); 1.96 (br t, J=10.0 Hz, 1H); 2.08 (dd, J=7.8, 4.1 Hz, 1H); 2.59
(br d, J=4.9 Hz, 2H); 2.68 (m, 2H); 3.21 (d, J=14.0 Hz, 1H); 3.27
(br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=14.2 Hz, 1H); 5.13 (s, 1H);
7.23 (d, J=7.4 Hz, 2H); 7.24 (d, J=5.6 Hz, 2H); 7.29 (d, J=8.2 Hz,
2H, partially obscuring doublet, 1H); 7.34 (br t, J=7.4Hz, 2H);
7.46 (d, J=8.1 2H); 8.49 (d, J=5.9 Hz, 2H).
EXAMPLE 13
[0169] 34
4-((alpha-S)-alpha-((2S,5R)-4-(4-Bromobenzyl)-2,5-dimethyl-1-piperazinyl)b-
enzyl)-N,N-diethylbenzamide
[0170] (Yield 89.87%). Calc. for C.sub.31H.sub.38BrN.sub.3O: C,
67.87; H, 6.98; N, 7.66; Br, 14.57. Found C, 68.00; H, 7.02; N,
7.68; Br, 14.44% .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.06 (d,
J=6.2 Hz, 3H); 1.10 (d, J=6.1 Hz, 3H, overlapping br m, 3H); 1.23
(br m, 3H); 1.94 (br t, J=9.4 Hz, 1H); 2.01 (dd, J=11.1, 8.1 Hz,
1H); 2.54 (m, 2H); 2.65 (d, J=9.2 Hz, 2H); 3.13 (d, J=13.4 Hz, 1H);
3.27 (br m, 2H); 3.54 (br m, 2H); 3.83 (d, J=13.5 Hz, 1H); 5.15 (s,
1H); 7.17 (d, J=8.1 Hz, 2H); 7.21 (d, J=7.5 Hz, 2H); 7.27 (d, J=6.2
Hz, 1H, partially obscured by CHCl.sub.3); 7.29 (d, J=8.1 Hz, 2H);
7.32 (br t, J=7.4 Hz, 2H); 7.39 (d, J=8.3 Hz, 2H); 7.46 (d, J=8.1
Hz, 2H).
EXAMPLE 14
[0171] 35
4-((alpha-S)-alpha-((2S,5R)-4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0172] (Yield 74.98%). Calc. for C.sub.31H.sub.38ClN.sub.3O: C,
73.86; H, 7.60; N, 8.34; Cl, 7.03. Found C, 73.76; H, 7.65; N,
8.22; Cl, 7.07% .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.06 (d,
J=6.1 Hz, 3H); 1.10 (d, J=6.1 Hz, 3H, overlapping br m, 3H); 1.23
(br m, 3H); 1.92 (br t, J=9.2 Hz, 1H); 1.98 (dd, J=11.0, 8.3 Hz,
1H); 2.54 (m, 2H); 2.65 (d, J=11.2 Hz, 2H); 3.15 (d, J=13.3 Hz,
1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.85 (d, J=13.2 Hz, 1H);
5.15 (s, 1H); 7.21 (m, 4H); 7.23 (d, J=7.2 Hz, 2H); 7.26 (m, 1H,
partially obscured by CHCl.sub.3); 7.29 (d, J=8.0 Hz, 2H); 7.33 (br
t, J=7.4 Hz, 2H); 7.46 (d, J=8.0 Hz, 2H).
EXAMPLE 15
[0173] 36
4-((alpha-S)-alpha-((2S,5R)-4-(2-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-
benzyl)-N,N-diethylbenzamide
[0174] (Yield 89.26%). Calc. for C.sub.31H.sub.38ClN.sub.3O: C,
73.86; H, 7.60; N, 8.34; Cl, 7.03. Found C, 73.70; H, 7.66; N,
8.30; Cl, 7.14% .sup.1H NMR (CDCl3, 600 MHz); .delta. 1.07 (d,
J=6.1 Hz, 3H); 1.12 (d, J=6.3 Hz, 3H, overlapping br m, 3H); 1.23
(br m, 3H); 1.96 (m, 1H); 2.12 (dd, J=11.1, 7.8 Hz, 1H); 2.60 (m,
1H), partially superimposed on 2.67 (d, J=7.1 Hz, 1H); 2.76(dd,
J=11.1, 2.3 Hz, 1H); 3.28 (br m, 2H); 3.38 (d, J=14.7 Hz, 1H); 3.54
(br m, 2H); 3.90 (d, J=14.5 Hz, 1H); 5.13 (s, 1H); 7.13 (dt, J=7.5,
1.3 Hz, 1H); 7.18 (t, J=7.4 Hz, 1H); 7.23 (d, J=7.4 Hz, 2H); 7.30
(d, J=8.2 Hz, 2H) superimposed on 7.30 (m, 2H) ; 7.33 (t, J=7.4 Hz,
2H); 7.48 (d, J=8.1 Hz, 2H) superimposed on 7.48 (m, 1H).
EXAMPLE 16
[0175] 37
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl-
)-benzyl)-N,N-diethylbenzamide
[0176] 4-Hydroxybenzaldehyde (488 mg, 4.0 mmol) was dissolved in a
solution of
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl-
)-N,N-diethylbenzamide (759 mg, 2.0 mmol, from Example 6, Method 1,
intermediate (c)) and acetic acid in tetrahydrofuran (10 mL).
Sodium triacetoxy borohydride (848 mg, 4 mmol) was added portion
wise over 5 min, then the reaction mixture sealed under nitrogen
and stirred overnight at room temperature. The reaction mixture was
evaporated to dryness and the residue partitioned between water (6
mL) and ethyl acetate (20 mL). The aqueous solution was further
extracted with ethyl acetate (2.times.10 mL) and the combined
extract and washings diluted with an equal volume of ether. The
organic solution was extracted with 3M-HCl and the acidic aqueous
solution carefully neutralized, initially with 5M-NaOH, then
saturated NaHCO.sub.3. At pH 4 the solution was filtered through a
0.45 mM syringe filter to remove a small quantity of an off-white
gummy solid. The pH of the filtrate was adjusted to 8.5 to
precipitate a flocculent white solid which was filtered off, washed
well with cold water and dried overnight at 2 mm Hg at room
temperature to yield
4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)-1-pipe-
razinyl)-benzyl)-N,N-diethylbenzamide (73.05%). Calc. for
C.sub.31H.sub.39N.sub.3O.sub.2 1.5H.sub.2O C, 72.62; H, 8.26; N,
8.20. Found C, 72.58; H, 7.83; N, 8.40% .sup.1H NMR (1% NaOD in
D2O, 300 MHz); .delta. 0.75 (br m, 3H); 0.81 (br d, J=7.3 Hz, 6H);
0.94 (br m, 3H); 1.71 (m, 1H); 1.84 (m, 1H); 2.29 (m, 2H); 2.49 (br
m, 2H); 2.91 (m, 3); 3.22 (m, 2H); 3.57 (br m, 2H); 5.02 (s, 1H);
6.39 (d, J=7.5 Hz, 2H); 6.80 (d, J=7.3 Hz, 2H); 7.01 (m, 7H); 7.17
(m, 2H).
EXAMPLE 17
[0177] 38
N,N-Diethyl-3-((S)-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)piperazin-1-yl-
)(phenyl)methyl)benzamide
[0178] 3-Carboxybenzaldehyde (150 g, 100 mmol) was weighed in a 250
mL, 3-necked, round bottom flask and stirred under nitrogen in 110
mL of toluene. Thionyl chloride (8.75 mL, 120 mmol) was added to
the mixture, followed by the addition of 6 drops of
dimethylformamide. A reflux condenser fitted with a calcium
chloride drying tube was placed on the flask. The reaction was
placed in an oil bath and heated at a bath temperature maintained
below 120.degree. C. The mixture was allowed to reflux for 1 hour
after a clear solution was obtained and then cooled to room
temperature. The solution was diluted with anhydrous toluene, and
all volatiles were removed under vacuum.
[0179] The crude acid chloride was dissolved in 200 mL of dry
tetrahydrofuran and cooled in an ice/water bath. Triethylamine
(27.88 mL, 200 mmol) in 70 mL of dry tetrahydrofuran was added
dropwise via an addition funnel, followed by diethylamine (10.45
mL, 100 mmol). The cloudy solution was allowed to warm to room
temperature over 1 hour and stirred overnight. Water was added and
the product was extracted with dichloromethane. The organic layer
was washed with water and saturated sodium chloride solution and
dried over sodium sulfate. The solvent was removed under vacuum to
give 3-formyl-N,N-diethylbenzamide (17.72 g) as a light golden oil
(86% crude yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
1.04-1.18 (m, 6H); 3.17-3.45 (m, 4H); 7.65-7.66 (m, 2H); 7.85 (s,
1H); 7.93-7.94 (m, 1H); 10.03 (s, 1H).
[0180] 2R,5S-1-allyl-2,5-dimethylpiperazine (6.99 g, 45.30 mmol,
Chirotech Technology, Ltd., Cambridge, England), benzotriazole
(5.45 g, 45.76 mmol, 1.01 eq.), and 3-formyl-N,N-diethylbenzamide
(9.30g, 45.30 mmol) were mixed in 300 mL of dry toluene with two
drops of triethylamine. The mixture was placed in an oil bath
maintained below 140.degree. C. (bath temperature. The flask was
attached to a Dean-Stark trap and reflux condenser to allow the
azeotropic removal of water. The mixture was refluxed for 2-3
hours, under a nitrogen atmosphere, then the majority of the
toluene was removed under reduced pressure. The crude adduct was
used in the following procedure without isolation. The crude
benzotriazole adduct was dissolved in 200 mL of tetrahydrofuran and
phenylmagnesium bromide (1 M in THF, 1.75 equiv.) was added via a
syringe. After stirring under nitrogen at room temperature for 2
hours, the reaction was quenched with 20 mL of saturated ammonium
chloride solution. After stirring for 30 min, a generous amount of
anhydrous magnesium sulfate was added. Filtering and concentrating
the solution under reduced pressure gave the crude product
contaminated with benzotriazole. This residue was dissolved in
ethyl acetate and extracted with 10% aqueous NaOH solution three
times to remove most of the benzotriazole. The organic layer was
washed with saturated sodium chloride solution, dried over sodium
sulfate/magnesium sulfate, and the ethyl acetate was removed under
reduced pressure. The crude material was chromatographed on silica
gel (20-25 g of silica gel per gram of crude material) eluting
first with methylene chloride, then with 20% ethyl acetate in
methylene chloride to remove the less polar contaminant. Then, the
column was eluted with a solution of ethyl acetate containing 2%
ammonium hydroxide (solution A) in a gradient with methylene
chloride (solution B), quickly increasing in polarity from 25% to
100% (solution A in B). The desired fractions were combined and the
solvent was removed under reduced pressure to give 5.52 g of
(+)-3-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)ben-
zyl)-N,N-diethylbenzamide was obtained as a golden oil. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta.0.96-0.98 (d, J=6.1 Hz, 3H);
0.98-1.15(m, 6H); 1.17-1.19(d, J=6.1 Hz, 3H); 1.80-1.85(t, 1H);
2.01-2.18 (m, 2H); 2.40-2.62 (m, 3H); 2.76-2.81 (m, 2H); 3.11-3.60
(m, 4H); 5.05-5.11 (dd, J.sub.1=6.1 Hz, J.sub.2=16.6 Hz, 2H); 5.16
(s, 1H); 5.75-5.90 (m, 1H); 7.14-7.17 (d, J=7.3 Hz, 1H); 7.21-7.47
(m, 8H).
[0181] The allyl portion was removed using Pd(dba)2/DPPB in the
presence of thiosalicylic acid by the method of Genet [J. P. Genet,
S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270
(1995)]. The reaction was concentrated and the residue was
dissolved in 50 mL ethyl acetate and 100 mL diethyl ether. After
washing this with Na.sub.2CO.sub.3 solution (3.times.100 mL) and
water (1.times.100 mL), the organic solution was extracted with 3 N
HCl (3.times.20 mL) and 1 N HCl (1.times.20 mL). The acidic extract
was adjusted to pH 8.5 using NaOH solution and extracted with
dichloromethane (3.times.25 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 4.30 g (11.32
mmol) of a viscous, deep amber-orange colored oil.
[0182] The above free amine (0.46 g, 1.21 mmol) and
4-hydroxybenzaldehyde (0.30 g, 2.42 mmol) were placed in a 50 mL
flask and sealed under nitrogen with 15 mL of tetrahydrofuran and
76.26 .mu.l of acetic acid (1.33 mmol, 1.10 equiv). The reaction
was stirred at room temperature for 20 minutes, and then sodium
triacetoxyborohydride (0.51 g, 2.42 mmol) was added and stirred for
4 hours. The reaction solution was poured into 100 mL of ethyl
acetate and washed with saturated NaHCO.sub.3 (100 mL) and brine
(80 mL). The solution was dried (Na.sub.2SO.sub.4/MgSO.sub.4) and
concentrated under reduced pressure. The residual light yellow oil
was purified by chromatography on silica gel
(EtOAc/CH.sub.2Cl.sub.2) to give 0.133 g (0.274 mmol) of the
desired product as a white amorphous solid. The salt was made by
dissolving the amine in ethanol and titrating to pH 3.92 with 0.2 M
HCl in ethanol. The salt was redissolved in water and lyophilized
to obtain a white powdery solid. .sup.1H NMR (300 MHz,
d.sub.6-DMSO): .delta. 0.94-1.28 (m, 12H); 1.80-2.05 (m, 2H);
2.40-2.69 (m, 4H); 3.06-3.25 (m, 3H); 3.42-3.60 (d, J=6.5 Hz, 2H);
4.44-4.48 (d, J=14.2 Hz, 1H); 5.47 (s, 1H); 6.78-6.81 (d, 2H);
7.13-7.55 (m, 11H); 9.78 (s, 1H). MS: 486.1 (M+1, 100%), 379.9
(10%). Calculated for C.sub.31H.sub.39N.sub.3O.sub.2 1.30 HCl &
1.10 H.sub.2O: C, 67.35; H, 7.75; N, 7.60; Cl, 8.34. Found: C,
67.37; H, 7.64; N, 7.47; Cl, 8.20.
EXAMPLE 18
[0183] 39
N,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)piperazin-1-yl)-
(3-methoxyphenyl)methyl)-benzamide
[0184] 2R,5S-t-allyl-2,5-dimethylpiperazine (9.08 g, 58.85 mmol,
Chirotech Technology, Ltd., Cambridge, England), benzotriazole
(7.08 g, 59.44 mmol, 1.01 eq), and 3-formyl-N,N-diethylbenzamide
(12.08 g, 58.85 mmol, Example 17) were mixed in 350 mL of dry
toluene with twenty drops of triethylamine. The mixture was placed
in an oil bath maintained below 140.degree. C. (bath temperature).
The flask was attached to a Dean-Stark trap and reflux condenser to
allow the azeotropic removal of water. The mixture was refluxed for
4 hours, under a nitrogen atmosphere, then the majority of the
toluene was removed under reduced pressure. The crude adduct was
used in the following procedure without isolation.
[0185] The crude benzotriazole adduct was dissolved in 200 mL of
tetrahydrofuran and 100 mL of 3-methoxyphenylmagnesium bromide (1 M
in THF, 1.70 equiv.) was added via a double-ended needle. The
reaction was slightly exothermic. Cooling in a room temperature
water bath gave a cloudy, yellow-brown reaction mixture. After
stirring under nitrogen at room temperature for 2 hours, the
reaction was quenched with 15 mL of saturated ammonium chloride
solution. After stirring for 30 min, a generous amount of anhydrous
magnesium sulfate was added. Filtering and concentrating the
solution under reduced pressure gave the crude product contaminated
with benzotriazole. This residue was dissolved in ethyl acetate and
extracted with 10% aqueous NaOH solution three times to remove most
of the benzotriazole. The organic layer was washed with saturated
sodium chloride solution, dried over sodium sulfate/magnesium
sulfate, and the ethyl acetate was removed under reduced
pressure.
[0186] The crude material was chromatographed on silica gel column
eluting first with methylene chloride, then with 10% ethyl acetate
in methylene chloride to remove the less polar contaminant. Then,
the column was eluted with a solution of ethyl acetate. The desired
fractions were combined and the solvent was removed under reduced
pressure to give 15.47 g of
3-((.alpha.R)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
-methoxybenzyl)-N,N-diethylbenzamide as a golden oil. .sup.1 H NMR
(300 MHz, CDCl.sub.3): .delta. 0.96-1.26 (m, 12H); 1.86-1.92(m,
1H); 2.07-2.14 (m, 1H); 2.36-2.45 (m, 1H); 2.57-2.59 (m, 2H);
2.62-2.86 (m, 2H); 3.23-3.53 (m, 5H); 3.77 (s, 3H); 5.11-5.22 (m,
3H); 5.76-5.91 (m, 1H); 6.71-6.81 (m, 3H); 7.20-7.33 (m, 5H).
[0187] The allyl portion was removed using Pd(dba)2/DPPB in the
presence of thiosalicylic acid by the method of Genet [J. P. Genet,
S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270
(1995)]. The reaction was concentrated and the residue was
dissolved in 50 mL ethyl acetate and 100 mL diethyl ether. After
washing this with Na.sub.2CO.sub.3 solution (3.times.100 mL) and
water (1.times.100 mL), the organic solution was extracted with 3 N
HCl (3.times.20 mL) and 1 N HCl (1.times.20 mL). The acidic extract
was adjusted to pH 8.5 using NaOH solution and extracted with
dichloromethane (3.times.25 mL). The solution was dried
(Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under reduced
pressure. The residual oil was purified by chromatography on silica
gel (2% NH.sub.4OH in EtOAc/CH.sub.2Cl.sub.2) to give 8.65 g (21.12
mmol) of a viscous, deep amber-orange colored oil.
[0188] A solution of
3-((.alpha.R)-.alpha.-((2S,5R)-2,5-dimethyl-1-piperaz-
inyl)-3-methoxybenzyl)-N,N-diethylbenzamide (0.49 g, 1.20 mmol) in
acetonitrile (10 mL) was added to sodium iodide (100 mg), sodium
carbonate (0.70 g, 6.64 mmol) and stirred under nitrogen at room
temperature during the addition of 3-fluorobenzyl bromide (0.16 mL,
1.32 mmol). The reaction was complete in 3 hours. The solvent was
removed by evaporation and the residue was partitioned between
methylene chloride and water. The aqueous layer was extracted with
methylene chloride twice more, and the combined organic extracts
were dried (Na.sub.2SO.sub.4/MgSO.sub.4) and concentrated under
reduced pressure. The residual brown oil was purified by
chromatography on silica gel (EtOAc/CH.sub.2Cl.sub.2) to give 0.37
g (0.71 mmol) of the desired product as a light brown amorphous
solid. The salt was made by dissolving the amine in ethanol and
titrating to pH 3.92 with 0.2 M HCl in ethanol. The salt was
redissolved in water and lyophilized to obtain a light brown
powdery solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.04-1.22
(m, 12H); 1.93-2.08 (m, 2H); 2.51-2.76 (m, 5H); 3.10-3.60 (m, 4H);
3.78 (s, 3H); 3.84-3.89 (d, J=13.3 Hz, 1H); 5.11 (s, 1H); 6.76-7.46
(m, 12H). MS: 518.0 (M+1, 60%), 296.0 (100%), 221.1 (60%).
Calculated for C.sub.32H.sub.40FN.sub.3O.sub.2 0.8 HCl: C, 70.28;
H, 7.52; N, 7.68; F, 3.47. Found: C, 70.19; H, 7.47; N, 7.62; F,
3.26.
EXAMPLE 19
[0189] 40
N,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)piperazin-1-yl-
)(3-methoxyphenyl)methyl)-benzamide
[0190] The title compound is made in identical fashion to the
compound of Example 17 by substituting phenylmagnesium bromide with
3-methoxyphenyl magnesium bromide.
EXAMPLE 20
[0191] 41
N,N-Diethyl-3-((R)-((2S,5R)-4-(3-chlorobenzyl)-2,5-dimethylpiperazin-1-yl)-
(3-methoxyphenyl)methyl)benzamide
[0192] The title compound is made in identical fashion to the
compound of Example 18 by substituting 3-fluorobenzyl bromide with
3-chlorobenzyl bromide.
EXAMPLE 21
[0193] The antidepressant-like activity of compounds of the present
invention was demonstrated by the forced swim test in rats, as set
forth below. The modified, Porsolt forced swim test has been
extensively used to evaluate antidepressant-like activity of
medicinal compounds. The Porsolt test was chosen as an assay
because of its strong correlation between a test compound's effect
on immobility time-shortening activity and antidepressant activity
in a rodent model and the antidepressant effect in humans.
[0194] The forced swim test was originally described by Porsolt
[Eur. J Pharmacology, 47, 379-391(1978)] and subsequently modified
by Lucki [Psychopharmacol., 119, 47-54 (1995)]. Swim sessions were
conducted by placing rats (five-week old male Sprague-Dawley rats
may be used) in plastic containers measuring 20 cm in diameter, 46
cm in height and filled to a depth of 30 cm with tap water at
23.degree. C.-25.degree. C. This water depth was sufficient to
prevent the rat from touching the bottom with its hind limbs or
tail or escape due to the tube height.
[0195] Two swim sessions were conducted for each testing rodent, a
15 min habituation swim, during which the test subject learned that
the tube was `inescapable`, and a 5 min test session 24 hours
later. The test session was videotaped for later scoring of escape
and immobility behaviors. The 5 minute test session was divided
into 5 second time bins and the predominant behavior was recorded
for each 5 sec bin (total 60 behavioral `counts`). The behaviors
scored were: swimming (exploration and investigation of escape
possibilities); climbing (attempting to scale the tube walls by
raising forelimbs out of water simultaneously and pawing at the
tube); and immobility (limited or no movement of the fore
limbs--making only those movements necessary to remain afloat with
hind limbs).
[0196] The compounds of the present invention were administered by
several routes including subcutaneously (s.c.), orally (p.o.), and
intravenously (i.v.). Drugs with antidepressant-like activity
decreased the number of time bins spent immobile (immobile counts)
and increased the number of active escape behavior counts (swimming
and/or climbing). The only procedural difference between oral,
subcutaneous and intravenous dosing was that of pretreatment time
(subcutaneously and orally=1 hr prior to test swim; intravenous=30
minutes prior to test swim). Control groups were administered the
relevant vehicle solution used to dissolve the compound tested.
Positive controls were run using known antidepressant compounds
including desipramine and buproprion.
[0197] Where the group variance was not different between test and
vehicle groups, pair wise comparison was made using a Student's
T-test. Where the variance was significantly different between
control and test groups, a Mann-Whitney U Test was used for pair
wise comparison.
[0198] The compounds of the present invention were unexpectedly
found to be active in the forced swim assay by decreasing
immobility and increasing swimming and/or climbing activity. These
results are similar to the results found in known antidepressants
when tested in the forced swim test. It is believed that the
results of increased activity and decreased immobility were
mediated through at least the delta opioid receptor, because it was
shown that the results exhibited in the forced swim test were
blocked by the delta opioid receptor antagonist naltrindole (data
not shown). These results provide statistically significant
evidence that the present compounds, administered by multiple
routes, possessed antidepressant activity.
[0199] Interestingly and unexpectedly some of the compounds of the
present invention caused an increase in both swimming and climbing
activity. Moreover, compounds of the present invention were found
to be effective as an antidepressant by oral administration and at
low dosages from about 1 to about 10 mg/kg, as shown below in Table
1.
1TABLE 1 Ex Dose Swimming Climbing Immobile No Compound (route)
counts counts counts 1 42 10 mg/kg (s.c.) 30 mg/kg (s.c.) 6.00 .+-.
2.03 3.40 .+-. 1.08* 22.17 .+-. 4.08* 17.40 .+-. 3.61* 31.83 .+-.
4.44* 39.20 .+-. 3.88* 7 43 10 mg/kg (i.v.) 30 mg/kg (i.v.) 9.67
.+-. 1.76 12.00 .+-. 3.42 22.50 .+-. 1.41* 23.75 .+-. 3.57* 26.83
.+-. 2.32* 24.25 .+-. 3.50* 4 44 10 mg/kg (p.o.) 30 mg/kg (p.o.)
29.4 .+-. 2.9* 32.3 .+-. 3.7* 10.1 .+-. 1.6 10.3 .+-. 2.5 20.5 .+-.
3.5* 17.4 .+-. 3.7* 2 45 1 mg/kg (p.o.) 3 mg/kg (p.o.) 13.9 .+-.
2.3 25.9 .+-. 2.5* 16.9 .+-. 4.1* 9.5 .+-. 1.6* 29.2 .+-. 5.4* 24.6
.+-. 33* 3 46 3 mg/kg (p.o.) 10 mg/kg (p.o.) 19.8 .+-. 3.8* 33.4
.+-. 3.3* 7.3 .+-. 1.6 8.4 .+-. 0.7 32.9 .+-. 5.1* 18.2 .+-. 3.8* 5
47 10 mg/kg (p.o.) 30 mg/kg (p.o.) 22.9 .+-. 4.0* 26.2 .+-. 3.9*
10.0 .+-. 3.5 8.7 .+-. 2.2 27.1 .+-. 4.3* 25.1 .+-. 5.0* *P <
0.05 compared to vehicle control.
[0200] While the invention has been described herein in reference
to specific aspects, features and illustrative embodiments of the
invention, it will be appreciated that the utility of the invention
is not thus limited, but rather extends to and encompasses numerous
other aspects, features and embodiments. Accordingly, the claims
hereafter set forth are intended to be correspondingly broadly
construed, as including all such aspects, features and embodiments,
within their spirit and scope.
* * * * *